San Francisco 49ers schedule and 2021 season predictions

San Francisco 49ers schedule takeaways:

  • The 49ers take on the Detroit Lions in Week 1 of the 2021 NFL season and boast the largest point spread right now.
  • With an early Week 6 bye, San Francisco will be forced to play 12 consecutive weeks to close out the regular season.
  • Sportsnaut predicts that the 49ers will finish with an 11-6 record.

The San Francisco 49ers schedule is now out, and it includes some dandies as Kyle Shanahan’s squad looks to rebound from an injury-plagued 2020 campaign.

Obviously, the focus in Santa Clara will be on a quarterback competition between incumbent starter Jimmy Garoppolo and rookie No. 3 pick Trey Lance.

This is likely where the 49ers are either going to get back to Super Bowl contention or remain a mediocre team. Of course, that’s also dependent on injuries not being the name of the game in 2021. Below, we break down the San Francisco 49ers schedule for the 2021 season and make score predictions for all 17 regular-season games.

San Francisco 49ers schedule predictions, roster outlook

San Francisco 49ers schedule
May 25, 2021; Santa Clara, CA, USA; San Francisco 49ers quarterbacks Trey Lance (5) and Jimmy Garoppolo (10) throw the football during Organized Team Activities at San Francisco 49ers Training Facility. Mandatory Credit: Stan Szeto-USA TODAY Sports

Let’s take a look at the team’s complete 2021 schedule and make predictions for each game.

49ers’ roster outlook

All of our predictions are based on the 49ers keeping and starting these key players:

  • QB — Jimmy Garoppolo, Trey Lance
  • RB — Raheem Mostert, Jeff Wilson (injured), Trey Sermon (rookie), Wayne Gallman, Elijah Mitchell (rookie)
  • FB — Kyle Juszczyk
  • TE — George Kittle, Ross Dwelley, Charlie Woerner
  • WR — Brandon Aiyuk, Deebo Samuel, Richie James, Mohamed Sanu, Jalen Hurd
  • Defense — 49ers ranked ninth in the NFL this week

The 49ers’ running back group is absolutely stacked, even after Jeff Wilson suffered an injury during offseason workouts. Former Ohio State star Trey Sermon is a player to watch here. He could excel big time in Kyle Shanahan’s system.

At wide receiver, the 49ers are expecting a big jump from second-year pass-catcher Brandon Aiyuk. They are also hoping stud receiver Deebo Samuel returns healthy after an injury-plagued 2020 sophomore campaign. These two could be an elite pairing.

Defensively, San Francisco returns star edge rusher Nick Bosa from a torn ACL he suffered early last season. Add in the presence of All-Pro linebacker Fred Warner and a rebuilt secondary, and this unit could help lead the 49ers to Super Bowl contention. The health of injury-plagued edge rusher Dee Ford will be vital here, too. He seems to be progressing after missing all but one game a season ago. If the Pro Bowler can return to form next to Bosa, the 49ers’ defense will be elite.

San Francisco 49ers 2021 preseason schedule

DateOpponentTime (ET)TV
Saturday, Aug. 14vs. Kansas City Chiefs8:30 PMKPIX 5
Sunday, Aug. 22@ Los Angeles Chargers7:30 PMKPIX 5
Sunday, Aug. 29vs. Las Vegas Raiders1:00 PMKPIX 5

This season the NFL is lowering the amount of preseason games to three per team, and instead expanding the regular season to 17 games, rather than the traditional 16 games.

Week 1 — @ Detroit Lions

DateTime (ET)TV
Sunday, Sept. 121:00 PM FOX
  • Spread: 49ers -7.5
  • Moneyline: Lions +300; 49ers -400
  • Over/under: 46

I am honestly not too sure how the Lions are going to rack up points without a ton of talent at the skill positions. That includes wide receiver. It also fits into the strength of San Francisco’s defense in the middle of the field. Without much of a threat outside, the likes of Fred Warner and Jimmie Ward can do damage in coverage. Add in Jared Goff’s struggles against this 49ers defense over the years, and it’s hard to envision a close game. 

  • Week 1 prediction: 49ers 31, Lions 13

Week 2 — @ Philadelphia Eagles

DateTime (ET)TV
Sunday, Sept. 191:00 PMFOX

Jalen Hurts will have a shiny new weapon in reigning Heisman winner Devonta Smith to toss the rock to as a sophomore. The hope here is that Philadelphia’s offensive line is more healthy than the 2020 iteration with its defense stepping up. Unfortunately, it’s that latter issue which could prove to be the Eagles’ downfall in 2021. Expect San Francisco to take advantage of that after giving a game away to the Eagles a season ago. 

  • Week 2 prediction: 49ers 31, Eagles 20

Week 3 — vs. Green Bay Packers (SNF)

DateTime (ET)TV
Sunday, Sept. 268:20 PMNBC

It’s going to be all about the status of Aaron Rodgers in Green Bay. With him aboard, the Packers are legit NFC title contenders. If Rodgers is indeed able to force his way from Wisconsin, this becomes a bottom-end playoff contender. Either way, these Packers have struggled big time against San Francisco in recent seasons. It’s just not a good matchup, with or without Rodgers in the mix. Expect the 49ers to take advantage of that with a huge Week 3 home win.

  • Week 3 prediction: 49ers 24, Packers 17

Week 4 — vs. Seattle Seahawks

DateTime (ET)TV
Sunday, Oct. 34:05 PMFOX

Kyle Shanahan is a mere 1-3 at home against Seattle at home against Seattle since taking over as the 49ers’ head coach. That must change if San Francisco wants to rebound following an injury-plagued 2020 season. The good news? These 49ers match up extremely well against the Seahawks — primarily on defense. A healthy Nick Bosa returning with All-Pro linebacker Fred Warner should do just enough against Russell Wilson and Co. to come out on top at home in this Week 4 matchup.

  • Week 4 prediction: 49ers 24, Seahawks 20
Seattle Seahawks' Russell Wilson
Kirby Lee-USA TODAY Sports

Week 5 — @ Arizona Cardinals

DateTime (ET)TV
Sunday, Oct. 104:25FOX

The 49ers and Cardinals have played competitive games over the past couple seasons. Last year saw Arizona win by four in Santa Clara to open the campaign and lose by eight at home later in the season. Back in 2019, San Francisco took both games by a combined 13 points. The moral of the story here? Expect a close affair with the Cards coming out on top at home. 

  • Week 5 prediction: Cardinals 24, 49ers 21


Week 7 — vs. Indianapolis Colts (SNF)

DateTime (ET)TV
Sunday, Oct. 248:20 PMNBC

Whether the San Francisco 49ers start Trey Lance or Jimmy Garoppolo, this figures to be a low-scoring game. Both teams want to win with their defense and controlling the clock. Long drives, plenty of field goals and Carson Wentz making just enough plays in the final minutes to secure a victory.

  • Week 7 prediction: Colts 23, 49ers 17

Week 8 — @ Chicago Bears

DateTime (ET)TV
Sunday, Oct. 311:00 PMFOX

Perhaps, this could be a matchup between Trey Lance and Justin Fields. However, it now seems more likely that Chicago will roll with Andy Dalton under center. If so, Matt Nagy’s squad is much too limited on offense to really make this a competitive game. Expect a 49ers win going away in the Windy City. 

  • Week 8 prediction: 49ers 31, Bears 20

Week 9 — vs. Arizona Cardinals

DateTime (ET)TV
Sunday, Nov. 74:25 PMFOX

Protecting the home field against fellow NFC West opponents is going to be a big deal for the 49ers in the ultra-competitive division. San Francisco is just 4-8 against said opponents at Levi’s Stadium since Kyle Shanahan took over in 2017. We’re expecting the team to flip the script in 2021. In this particular matchup, the 49ers’ defensive line will have a distinct advantage over the Arizona offensive line in front of Kyler Murray and be able to lead to a season split.

  • Week 9 prediction: 49ers 28, Cardinals 24

Week 10 — vs. Los Angeles Rams (MNF)

Monday, Nov. 158:15 PMESPN

Two of the favorites in the NFC West heading into the 2021 NFL season, whoever comes out on top in this division will have to take care of business in their head-to-head matchups. Unfortunately for the 49ers, Los Angeles seemingly has matchup advantages clear across the board. That includes Cooper Kupp and Robert Woods taking advantage of slower-footed 49ers cornerbacks and the presence of Aaron Donald against a still-questionable interior of the 49ers’ offensive line. 

  • Week 10 prediction: Rams 31, 49ers 27

Week 11 — @ Jacksonville Jaguars

DateTime (ET) TV
Sunday, Nov. 211:00 PMFOX

Another potential matchup between two rookies, Trevor Lawrence is the sure-fire starter for Jacksonville. He also has a ton of weapons and a solid offensive line in front of him. At the very least, that should make Jacksonville competitive against better teams after losing its final 15 games a season ago. Unfortunately, the defense remains a major question-mark. Whether it’s Jimmy Garoppolo or Trey Lance under center for the 49ers, they should score enough to win in Duval. 

  • Week 11 prediction: 49ers 34, Jaguars 23
NFL storylines: Trevor Lawrence
Logan Bowles/NFL Handout photo via USA TODAY Network

Week 12 — vs. Minnesota Vikings

DateTime (ET)TV
Sunday, Nov. 284:25 PMFOX

I am still not sold on Kirk Cousins being able to go to into Levi’s Stadium against a fully-healthy 49ers defense and accomplishing a darn thing. His last appearance against this unit led to an historically bad Vikings performance on offense. With Nick Bosa back and questions lingering on the Vikings’ offensive line, look for a narrow San Francisco home win.

  • Week 12 prediction: 49ers 24, Vikings 17

Week 13 — @ Seattle Seahawks (SNF)

DateTime (ET)TV
Sunday, Dec. 58:20 PMNBC

The recent history of this rivalry is interesting. Last season saw the 49ers lose by a mere three points in Seattle despite Garoppolo going down to an injury. Back in 2019, it clinched the NFC West with a dramatic win over the Seahawks in the Pacific Northwest in Week 17. What does this mean? Despite holes for both the Hawks and 49ers heading into 2021, we can expect close games. Look for Russell Wilson and Co. to hold court at home. 

  • Week 13 prediction: Seahawks 31, 49ers 23

Week 14 — @ Cincinnati Bengals

DateTime (ET)TV
Sunday, Dec. 121:00 PMCBS

At the very least, Cincinnati should be fun in 2021. Last year’s No. 1 pick, Joe Burrow, is slated to return completely healthy after suffering a torn ACL in 2020. He’ll have rookie No. 5 pick Ja’Marr Chase to toss the rock to. Add in Tee Higgins, and this offense could be good. Unfortunately, the Bengals’ defensive front seven is a hot mess after their defense yielded nearly four touchdowns per game in 2020. The 49ers will take advantage of this. 

  • Week 14 prediction: 49ers 34, Bengals 20
San Francisco 49ers schedule: Cincinnati Bengals, Joe Burrow
Sam Greene/Cincinnati Enquirer-USA TODAY NETWORK

Week 15 — vs. Atlanta Falcons

DateTime (ET)TV
Sunday, Dec. 191:00 PM CBS

The Kyle Shanahan game. Could this be Atlanta’s way of finally proving it has moved on from that era of Falcons football? I am not buying it in this Week 15 matchup in California. Whether it’s Jimmy Garoppolo or Trey Lance under center, these 49ers have way too much firepower on offense for the Falcons to be able to stay afloat.

  • Week 15 prediction: 49ers 35, Falcons 17

Week 16 — @ Tennessee Titans (TNF)

DateTime (ET)TV
Thursday, Dec. 238:20 PMNFL Network

Here’s an interesting stat. Ryan Tannehill is 18-8 as the Titans’ starter since joining the team back in 2019. Since the start of the 2014 season, all other Titans quarterbacks boast a combined 34-52 record as starters. There’s just something about Tannehill sharing a backfield with Derrick Henry. In and of itself, that should be enough for Tennessee to come out on top at home in what will be a hotly-contested affair. Add in the presence of Julio Jones against a now-questionable 49ers cornerback group, and it will lead to a Titans win.

  • Week 16 prediction: Titans 24, 49ers 21

Week 17 — vs. Houston Texans

DateTime (ET)TV
Sunday, Jan. 21:05 PMCBS

This could get laughably bad, especially if the 49ers are playing for postseason positioning and the Texans end up being as bad as we envision. Now that there’s a good chance Deshaun Watson could be forced to sit out the 2021 season, that’s magnified further. In fact, I wouldn’t be surprised if the 49ers ended up resting some of their starters after the first half in this home outing.

  • Week 17 prediction: 49ers 42, Texans 10

Week 18 — @ Los Angeles Rams

DateTime (ET)TV
Sunday, Jan. 94:25 PM FOX

Los Angeles won both games against its division rivals a season ago by a combined 11 points. That’s despite the fact Jared Goff threw two touchdowns against three interceptions in those matchups. With Matthew Stafford acting as a major upgrade under center in 2021, this won’t be a problem. At the very least, it should allow the Rams to protect their home-field in this matchup. 

  • Week 18 prediction: Rams 28, 49ers 24

San Francisco 49ers projected record: 11-6