DEN vs SF Prediction, Odds and NFL Picks for Sunday, 10/04/26

The San Francisco 49ers will be trying to remain undefeated when they host the Denver Broncos in Week 4 of the NFL season on Sunday afternoon. Returns are early, but San Francisco is arguably looking like the best team in football through three games. As such, my Broncos vs 49ers pick is on the home team to win and cover. The Niners defeated their first trio of opponents by a combined 48 points. Brock Purdy is playing at an MVP level and head coach Kyle Shanahan's squad finally has something close to a clean bill of health on the defensive side of the ball. 

It’s hard to be convinced by a 2-1 Denver club even though it managed to “beat” the Rams this past Sunday night. And, yes, “beat” belongs in quotes. The Broncos were playing at home and did not have to deal with either defensive end Myles Garrett or wide receiver Puka Nacua, and they still needed significant help from the officials to survive 30-26 in a thriller that came down to the final play. It would have been over several minutes earlier if L.A. cornerback Josh Wallace had been correctly awarded a game-clinching interception instead of getting hit with an incorrect pass interference call. Denver’s only foray away from home so far this season resulted in a 31-10 loss at Kansas City, so I can’t see the visitors staying with a field goal on the road against what is currently the best team in the NFC.

Denver Broncos vs San Francisco 49ers prediction: 49ers -2.5 (-115) available at time of publishing. Playable to -3.