Broncos vs. 49ers Prediction, Odds, Spread, Injuries, Trends for NFL Week 4

Two of the best teams in the NFL face off in Week 4.

The Denver Broncos an quarterback Bo Nix are underdogs in Week 4. | IMAGN IMAGES via Reuters Connect

Arguably the best matchup in NFL Week 4 will take place in San Francisco, as the Denver Broncos and Bo Nix hit the road to take on Brock Purdy and the San Francisco 49ers. 

Denver is off to an impressive 2-1 start after facing the Kansas City Chiefs (a loss), Jacksonville Jaguars and Los Angeles Rams to open the 2026 season. Denver’s tough schedule continues with the undefeated 49ers up next, but Bo Nix and Co. have found ways to pull out comeback wins in back-to-back weeks. 

San Francisco is climbing in the odds to win the Super Bowl after the Rams and Seattle Seahawks both lost in Week 3, and it’s favored at home in this matchup. Brock Purdy (second in the MVP odds) has been on fire in 2026, and he’ll be a tough matchup for a Denver defense that has allowed some big scoring games to L.A. and Kansas City through three weeks. 

After beating the Rams in Week 1, the 49ers have benefitted from two easy games against Miami and Arizona, though they failed to cover at home against the Cardinals in Week 3. The 49ers also left that game with Nick Bosa already ruled out for Week 4 and Mike Evans, Trent Williams, Dre Greenlaw and others injured. 

That could be a major concern against a Denver team that made the AFC title game last season and is starting to turn a corner on offense after a dreadful Week 1 performance. 

Oddsmakers have the 49ers favored at home in this matchup, and both teams are 2-1 against the spread in 2026. 

Here’s a breakdown of the odds, a player prop to bet and my prediction for this marquee matchup in Week 4.  

Broncos vs. 49ers Odds, Spread and Total

Odds via DraftKings Sportsbook

Spread

• Broncos +3 (-115)
• 49ers -3 (-105)

Moneyline

• Broncos: +130
• 49ers: -155

Total

• 46.5 (Over -112/Under -108)

Broncos vs. 49ers How to Watch

• Date: Sunday, Oct. 4 
• Time: 4:25 p.m. EST
• Venue: Levi’s Stadium
• How to Watch (TV): CBS
• Broncos record: 2-1
• 49ers record: 3-0

Broncos vs. 49ers Injury Reports

Broncos Injury Report

• Jonathon Cooper – Commissioner’s Exempt List
• Marvin Mims Jr. – questionable
• Jonah Coleman – IR

49ers Injury Report

• Nick Bosa – out
• James Thompson Jr. – out
• Dre Greenlaw – questionable
• Mike Evans – questionable
• Romello Height – questionable
• Demarcus Robinson – IR
• Trent Williams – questionable
• Gracen Halton – questionable

Broncos vs. 49ers Betting Trends

• The Broncos are 2-1 against the spread this season.
• Denver is 1-1 against the spread as an underdog in 2026.
• The 49ers are 2-1 against the spread this season.
• The 49ers are 1-1 against the spread as home favorites in 2026.
• The OVER is 2-1 in the 49ers’ three games in 2026.
• The UNDER is 2-1 in the Broncos’ three games in 2026. 

Broncos vs. 49ers Key Player to Watch

Brock Purdy, Quarterback, San Francisco 49ers

Purdy is now the No. 2 candidate in the odds to win MVP, as he turned in yet another monster game in a win over Arizona on Sunday.

Purdy has benefitted from back-to-back easy games against the Dolphins and Cardinals, but he’s still completed well over 70 percent of his passes for 789 yards, nine scores and one pick. He’s also added 93 yards and a score on the ground. 

With Mike Evans banged up, it’ll be interesting to see how Purdy fares against Pat Surtain II, Riley Moss and this vaunted Denver secondary. The Broncos are still 10th in the NFL in EPA/Pass despite facing Patrick Mahomes, Trevor Lawrence and Matthew Stafford to open the season. 

Purdy has come down from +850 to +450 to win MVP after leading San Francisco to a 3-0 start.

Broncos vs. 49ers Prediction and Pick

The 49ers are off to a 3-0 start and have the No. 1 offense in EPA/Play in the league, yet the schedule gets a lot tougher with this Week 4 matchup and a Week 5 date against Seattle. 

I’m worried about this San Francisco defense without Bosa (and potentially Greenlaw) against a Denver team that is a lot better than Miami and Arizona. The 49ers are just 19th in success rate and 15th in EPA/Play this season, a shaky ranking since they’ve faced two of the worst teams in the NFL.

Meanwhile, Denver is 10th in EPA/Pass despite facing three quarterbacks in the MVP conversation. The Bronco offense hasn’t been anywhere near as good as the 49ers, but is San Francisco’s offense being propped up by favorable matchups? 

I don’t think that’s entirely the case, but it helps that the 49ers have faced the No. 28 (Arizona) and No. 29 (Miami) defenses in EPA/Play. Those teams also rank in the bottom five in the NFL in yards per play allowed.

Denver really flipped the script on offense in the second half against the Rams, and the defense was great all game, bending but not breaking against Matthew Stafford and Co. 

The 49ers are rightful favorites on Sunday, but with this spread sitting at a field goal, I’ll take the points with Nix and the Broncos. 

Pick: Broncos +3 (-115 at DraftKings)

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