The season saw many key players missing significant time due to injuries, including starting quarterback Jimmy Garoppolo, starting tight-end George Kittle, starting cornerback Richard Sherman, starting wide receiver Deebo Samuel, and 2019 Defensive Rookie of the Year Nick Bosa.[2] The 49ers season ended with a league-high 18 players on injured reserve. Another notable event was the suspension of home games in Santa Clara County due to the ongoing COVID-19 pandemic, forcing the 49ers to play their final three home games at State Farm Stadium in Glendale, Arizona.
The 49ers traded their first- and a seventh-round selection (13th and 245th overall) to Tampa Bay Buccaneers in exchange for a first- and a fourth-round pick (14th and 117th overall).[57]
The 49ers traded their first-, fourth- and fifth-round selections (31st, 117th and 176th overall) to Minnesota Vikings in exchange for a first-round pick (No. 25th overall).[58]
The 49ers traded their WRMarquise Goodwin and a sixth-round selection (No. 210th overall) to Philadelphia Eagles in exchange for a sixth-round selection (No. 190th overall).[62]
Although the 49ers won easily over the struggling Jets, they suffered devastating injuries on both sides of the ball to Jimmy Garoppolo, Raheem Mostert, Tevin Coleman, Nick Bosa, and Solomon Thomas.[65] It got so bad the team's MRI truck broke down. The win brought the 49ers to 1-1 on the season.
With Jimmy Garoppolo sidelined, Nick Mullens made his first start since 2018. He threw for 343 yards and a touchdown in a blowout win over the Giants, bringing the 49ers up to 2-1 for the season.
With this loss, the 49ers dropped to 2–2. Nick Mullens struggled mightily in the game with two interceptions, one of which was returned by Alex Singleton for a touchdown, and was benched afterwards for C. J. Beathard. The 49ers drove all the way to within field goal range down by 5, but the clock ran out.
With this embarrassing loss, the 49ers dropped to 2–3, already matching last season's loss total. Jimmy Garoppolo returned from injury but struggled mightily with 2 interceptions, leading to him being benched at halftime for C. J. Beathard.
The 49ers bounced back from the previous week. Jimmy Garoppolo threw 3 touchdowns and 268 yards and the 49ers defense was able to hold a red-hot Rams offense in check. With this win, they improved to 3–3, and won their third straight meeting against the Rams.
This was quarterback Jimmy Garoppolo's first return to New England since the Patriots traded him to the 49ers in October 2017. Garoppolo played for the Patriots from 2014 to 2017, and was part of their 2014 and 2016 Super Bowl-winning teams. Jimmy's victorious return brought the 49ers up to 4-3 on the season.
In a rematch of the NFC Championship the previous season. Aaron Rodgers threw for 305 yards and 4 touchdowns as the Packers went up 34–3 before the 49ers scored two meaningless touchdowns to make the final score 34–17 and dropping the 49ers to 4–5. As of week 9, the 49ers have a league high 24 players on the reserve lists.[66][67] Due to the Covid 19 pandemic restrictions, this would be the final game at Levi's for the season.
The 49ers returned from their bye week with some much-needed reinforcement returning from injury: on offense, Raheem Mostert scored a touchdown and 43 yards rushing and Deebo Samuel had 133 receiving yards; on defense, Richard Sherman contributed by grabbing his first interception of the season. The game was largely a defensive struggle. The two teams had four combined turnovers in the first quarter, and the only points scored in the first half came on a Raheem Mostert touchdown and a Matt Gay field goal. Early in the third quarter, the 49ers padded their lead to fourteen points with Javon Kinlaw's pick six and a Robbie Gould field goal. However, the momentum changed quickly as Aaron Donald forced a fumble on Raheem Mostert and it was returned for a touchdown by Troy Hill. The Rams soon scored again on a touchdown run from Cam Akers to take a three-point lead. The Rams' final drives quickly turned to punts while Nick Mullens led the 49ers on two drives resulting in field goals, including the 42-yard game winner by Robbie Gould with no time on the clock.
With the win, the 49ers swept the Rams for the second straight year and bringing their record to 5-6
In a game that saw a returning Alex Smith to face the team that drafted him for the final time and Smith's revenge dropped the 49ers to 5-8 on the season.
The 49ers traveled to Dallas hoping to keep their season alive, but struggled throughout the game. The 49ers immediately trailed 17–7, and turned the ball over 4 times against one of the worst defenses in the NFL. Despite fighting back and forth after tying the game, the 49ers never had the lead. San Francisco also allowed Cowboys wide receiver CeeDee Lamb to return a kickoff for a touchdown, which sealed the 49ers' loss. This loss, combined with the Cardinals' victory over the Eagles, eliminated the 49ers from playoff contention. The 49ers also clinched a losing season for the 7th time in 10 years.
With this loss, the 49ers finished 1-7 at home and are 1-5 in their last 6 games against Seattle. The Defending NFC Champions would finish their season in dismissal 6-10 record.
^ abNew Orleans finished ahead of Seattle based on conference record.
^ abChicago finished and clinched the 7th and final playoff spot ahead of Arizona based on better win percentage in common games (against Detroit, the NY Giants, Carolina, and the LA Rams, Chicago finished 3–2, while Arizona finished 1–4).
^ abSan Francisco finished ahead of the NY Giants based on head-to-head victory. Division tie break was initially used to eliminate Dallas (see below).
^ abNY Giants won tiebreaker over Dallas based on division record.
^ abCarolina finished ahead of Detroit based on head-to-head victory.
^When breaking ties for three or more teams under the NFL's rules, they are first broken within divisions, then comparing only the highest-ranked remaining team from each division.
^ abcdefgOn November 30, Santa Clara County imposed a ban on all contact sports for three weeks, later extended through January 8, due to rising COVID-19 cases. As a result, the 49ers were forced to play home games and practice from out-of-county. The team used Arizona's State Farm Stadium as a temporary venue for the remainder of the season.[64]