The 3-0 49ers host the 2-1 Broncos on Sunday, Oct. 4 at 1:25 p.m. PT at Levi’s Stadium, with San Francisco favored by 2.5 points.
My Broncos vs. 49ers prediction highlights why this matchup favors San Francisco, while this week’s NFL picks include a top play tied to the Niners’ early-down dominance.
TOP PICK
Broncos vs 49ers prediction: 49ers -2.5
According to my power ratings, the San Francisco 49ers -2.5 are by far the best team in the NFL, and they're tradable up to -4 against the Denver Broncos. San Francisco leads the league in both net yards per play and net early-down EPA per play.
Early-down EPA is my favorite metric because the entire playbook remains available on first and second downs. The gap between the Niners and Denver, which ranks 11th in early-down EPA per play, is larger than the gap between the Broncos and the worst team in the league.
Denver is ninth in added win probability via luck, per NFL data scientist Tom Bliss. That doesn't account for the controversial officiating decisions in Sunday's win over the Los Angeles Rams, a team San Francisco crushed in Week 1.
COVERS INTEL: The Niners have a strength-on-weakness edge on the ground: San Francisco ranks fourth in yards per rush, while Denver's defense is 30th in yards per carry allowed. 
Broncos vs 49ers combo
I'm opting for San Francisco's moneyline instead of the spread to increase my win probability and protect against a close game. Niners RB Christian McCaffrey's anytime touchdown usage is straightforward: CMC is one of the most dangerous offensive weapons in the NFL and can score on the ground or through the air.
The final leg also correlates with San Francisco winning. Broncos RB J.K. Dobbins has struggled this season, isn't a bellcow, and faces a Niners defense that has been strong against the run. If San Francisco plays from ahead as I expect, Denver could be forced to throw more in the second half, further reducing Dobbins' rushing opportunities.
Broncos vs 49ers combo
- San Francisco moneyline
- Christian McCaffrey anytime touchdown
- J.K. Dobbins Under 59.5 rushing yards
Broncos vs 49ers touchdown scorer: Deebo Samuel
Niners WR Deebo Samuel Sr.'s anytime touchdown prop is playable up to 40% because Kyle Shanahan uses him in so many ways. Last week, Samuel cashed a touchdown prop for me by scoring on an 80-yard hook-and-lateral with WR Mike Evans.
Plus, Deebo gets carries and has 22 rushing touchdowns for his career. He is playing the highest percentage of snaps among San Francisco's wide receivers, and two 49ers wideouts missed practice Wednesday and Thursday, including Evans. That could lead to even more usage for Samuel on Sunday.
- Top picks: 2-8, -6.19 units
- Combos: 2-8, -0.5 units
Broncos vs 49ers odds
For help understanding probabilities, see our odds calculator.
- Spread: Broncos +2.5 | 49ers -2.5
- Over/Under: Over 48.5 (51%) | Under 48.5 (54%)
- Moneyline: Broncos 46% | 49ers 59%
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Broncos vs 49ers weather
It's expected to be 86° in the Bay Area on Sunday, with a light four mph wind and no chance of rain.
Check out our NFL weather page for up-to-date info on every matchup.
Broncos vs 49ers trend to know
The Niners are 5-0 against the spread in their last five games following a non-cover. Find more NFL betting trends for Broncos vs. 49ers.
How to watch Broncos vs 49ers
| Location | Levi's Stadium, Santa Clara, CA |
| Date | Sunday, Oct. 4, 2026 |
| Kickoff | 4:25 p.m. ET |
| TV | CBS |
Broncos vs 49ers latest injuries
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