The undefeated San Francisco 49ers host the 2-1 Denver Broncos in Week 4, and the matchup has more intrigue than the records alone suggest. San Francisco scored 36 against Arizona, while Denver beat the Rams 30-26.
The 49ers are favored, but Nick Bosa is out, Mike Evans is nursing a rib injury, and Denver’s defense just supplied a game-changing touchdown. These are three bold, standout predictions for Sunday at Levi’s Stadium, each built around an unlikely individual performance.
Jaylen Waddle explodes for 150 yards and two touchdowns
Waddle followed an eight-catch, 138-yard Week 2 breakout with two catches for 10 yards against the Rams. As for this week goes, he tops 150 receiving yards and scores twice.
The opportunity is there even after the quiet game. Waddle drew seven targets against Los Angeles, tied for the team lead. Bo Nix managed only 186 passing yards and an interception, so the Broncos need more than a couple of routine completions from their biggest-play threat.
San Francisco’s defense is missing Bosa, its premier edge rusher, and defensive tackle James Thompson Jr. is also out. The 49ers allowed Arizona to make the Week 3 meeting a one-score game late, despite a commanding lead. That gives Nix a better chance to wait for Waddle to cross the field or break open deep.
Denver cannot count on another defensive touchdown. If Nix gets time, Waddle can turn a frustrating Week 3 into the kind of explosive afternoon that changes both the game and the conversation around Denver’s passing attack.
Talanoa Hufanga intercepts Brock Purdy twice
Hufanga was Denver’s Week 3 hero, picking off Matthew Stafford twice and returning one interception 66 yards for a touchdown. Now the former 49ers safety returns to face the team that drafted him. This week he keeps it going with two more interceptions, including one in the fourth quarter.
Former #49ers S Talanoa Hufanga just pick 6’d a Matthew Stafford pass…
We see you HUF!!!!! pic.twitter.com/w9tmzu5UXt
— 49ers & NFL News 24/7 (@49ersSportsTalk) September 28, 2026
Purdy has been exceptional through three games, with 789 passing yards, nine touchdowns and just one interception. He threw four scores against Arizona, and George Kittle caught two of them. But the 49ers lost Evans to a rib injury during that win, and left tackle Trent Williams exited with a stinger. Evans is day-to-day, so San Francisco’s lineup remains worth monitoring.
If the wideout cannot play or is limited, Purdy may rely even more heavily on Kittle and Christian McCaffrey. Hufanga has the instincts to jump a familiar route over the middle, especially if Denver’s rush forces an early throw. Two picks against Purdy would be extraordinary, but Denver has reasons to test him.
RJ Harvey scores twice as Denver wins 34-27
Harvey had only two carries for six yards against the Rams. Those numbers hardly scream breakout, but he caught six of seven targets for 41 yards in his return from a hamstring injury. He was evaluated for a concussion during the game and cleared to return. That receiving role gives Sean Payton another way to attack.
Harvey scores one receiving touchdown and one rushing touchdown, and the Broncos hand the 49ers their first loss, 34-27. San Francisco surrendered 30 points to Arizona in Week 3, and its defensive injuries create an opening for Denver to spread the field, then attack the goal line with Harvey.
The 49ers will have answers. McCaffrey produced 116 scrimmage yards and a touchdown against the Cardinals, while Kittle caught six passes for 82 yards and two scores. A Broncos upset would require Nix to keep pace, not merely ask Hufanga for another rescue act. Harvey’s work as a receiver could be the surprise that tips the balance. San Francisco cannot focus solely on Waddle.