Denver Broncos at San Francisco 49ers
Sunday, October 4, 2026
4:25 PM ET, Levi’s Stadium
San Francisco is a 2.5-point home favorite over Denver with a total of 47.5. My play is the Broncos getting the points.
Nick Bosa’s absence is the entry point here. The 49ers’ best defensive player has been ruled out, and left tackle Trent Williams, linebacker Dre Greenlaw and wide receiver Mike Evans are all questionable. Losing Bosa takes away San Francisco’s most reliable source of pressure against a Denver offense that has needed time to get going in every game this season. If Williams can’t go either, the 49ers are missing key pieces on both sides of the line.
Denver’s defense is the reason the Broncos can hang in this game. Denver has racked up 139 sacks since the start of the 2024 season, 27 more than any other team, and the unit ranks 10th in EPA per pass this year despite facing Patrick Mahomes and Matthew Stafford. Talanoa Hufanga also gets a revenge game against the team that let him walk in free agency, and he’s coming off a sack and two interceptions against the Rams, including a 66-yard pick-six.
The 49ers’ 3-0 start comes with an asterisk. They beat the Rams 27-7 in Melbourne, the Dolphins 35-13 and the Cardinals 36-30, and Miami and Arizona rank 28th and 29th in defensive EPA per play. Denver is the first good defense San Francisco has seen. The 49ers’ offensive line hasn’t allowed a sack through three games, and Brock Purdy leads the NFL with nine touchdown passes, but those numbers came against defenses that couldn’t generate pressure. Denver can.
The BEST 2026 Football Bonus: Deposit $100 to $1000 and get a 75% real cash bonus when you deposit using Bitcoin at Bovada Sportsbook!
Denver’s offense is the question mark. The Broncos have trailed at halftime in all three games, including 16-0 at the break against the Rams before rallying for a 30-26 win. Bo Nix is completing 60.2% of his passes at 6.5 yards per attempt with four touchdowns and three interceptions, and Sean Payton has said he’s uncomfortable with how his team starts games. But this team has shown it can finish. Denver beat Jacksonville 20-13 in Week 2 behind Nix’s best game (22 of 31 for 288 yards) and came all the way back on the road in Week 3.
San Francisco’s offense is elite. The 49ers lead the NFL in yards per play (7.35) and success rate, they’re second in scoring at 32.7 points per game, and they haven’t turned the ball over in 11 straight quarters. That’s the biggest risk to this pick. But without Bosa on the other side of the ball, San Francisco is more likely to be in a close game than a blowout.
The last time these teams met, in 2022, Denver won 11-10. Both teams are 2-1 against the spread this season, and the Broncos’ formula of defense, pressure and late-game execution is built for a game decided by a field goal.
Realistic outcomes: 49ers 24, Broncos 23 (1-point margin, Broncos cover +2.5); Broncos 23, 49ers 20 (Broncos win outright); 49ers 27, Broncos 26 (1-point margin, Broncos cover); or 49ers 28, Broncos 20 (8-point margin, doesn’t cover). Three of four scenarios cover for Denver.
The Pick: Denver Broncos +2.5
Back the Broncos and the points against a 49ers team without Nick Bosa, and bring some extra bankroll into the late window. New players at MyBookie Sportsbook get a 100% REAL CASH bonus on a first deposit of $100 to $300 with promo code PREDICT100. That’s a FREE way to bet Denver +2.5 and the rest of your Week 4 NFL picks.
