NFL Upset Predictions and Picks for Week 16 (Can Philip Rivers Lead Colts to Upset Win Over 49ers?)

Iain MacMillan | 2 Hours Ago

The Colts are +240 underdogs to the 49ers in Week 16. / Rivers: Kevin Ng-Imagn Images, Purdy: Kyle Terada-Imagn Images

Upsets have some extra juice to them in the final stretch of the season, as they could have a significant impact on the postseason picture. Last week, Gilberto Manzano cashed in on the Los Angeles Chargers to upset the Kansas City Chiefs, which officially eliminated Patrick Mahomes and Co. from playoff contention.

We move on to Week 16 and the SI team is back to break down their favorite upset picks for this weekend's slate of games.

Odds via FanDuel Sportsbook

• Matt Verderame, NFL Staff Writer
• Gilberto Manzano, NFL Staff Writer
• Iain MacMillan, Senior Editor, Betting
• Peter Dewey, Associate Managing Editor

Matt Verderame Week 16 Upset Pick

Tennessee Titans (+144) vs. Kansas City Chiefs

If there’s ever been a team that is more emotionally and physically drained than the 2025 Chiefs, good luck finding them. Kansas City is beyond cooked, playing meaningless football for the first time since the final game of the 2012 season.

The Chiefs are without Patrick Mahomes, and while the Titans are a two-win disaster, most of those players are trying to put out good film to either impress the Tennessee coaching staff or another team around the league. Kansas City is a team full of veterans who assuredly can’t wait to hit the golf course and reset after one of the most lackluster seasons we’ve seen in recent memory from a team expected to compete for a title.

Gilberto Manzano Week 16 Upset Pick

Indianapolis Colts (+240) vs. San Francisco 49ers

I was impressed with the game plan coach Shane Steichen and 44-year-old Philip Rivers put together to play ball control against a dominant Seahawks defense. The matchup will get easier against a short-handed 49ers defense, but defensive coordinator Robert Saleh can certainly hang in a chess match vs. Rivers and Steichen. 

It’s going to take a monster performance from Jonathan Taylor for the Colts to end their four-game losing streak. Taylor can deliver that kind of game with Rivers as a coach on the field to direct traffic.

Iain MacMillan Week 16 Upset Pick

Indianapolis Colts (+240) vs. San Francisco 49ers

Philip Rivers is back in action, and while he may not have looked like his old gunslinger self, he's still extremely smart and will make very few mistakes. People are also quick to forget that he had to face one of the best defenses in the NFL in his first game since 2021. Now, he has a much easier matchup ahead of them against the injured 49ers defense that ranks in the bottom 10 of the NFL, especially when it comes to stopping the run.

Daniel Jones' injury didn't break this Colts team. The Colts still rank fourth in overall DVOA and sixth in Net Yards per Play. It could also be time to sell high on this 49ers team. Don't be surprised if Indianapolis pulls off this upset and keeps its playoff hopes alive.

Peter Dewey Week 16 Upset Pick

Carolina Panthers (+130) vs. Tampa Bay Buccaneers

The NFC South is on the line over the next three weeks, and I’m buying the Carolina Panthers and Bryce Young as home underdogs on Sunday against the Tampa Bay Buccaneers.

There are some interesting trends to consider in this game, especially with Tampa Bay going 2-6 over its last 10 games:

• Carolina is 4-2 against the spread at home.
• The Panthers are 7-4 against the spread as underdogs.
• Tampa Bay is just 2-5 against the spread as a favorite.

I wouldn’t be shocked if Carolina keeps this game within a possession. Tampa Bay has slipped behind the Panthers in EPA/Play on offense (now 24th), and the Bucs are also just 18th in the league in EPA/Play on defense.

The Panthers outrank Tampa Bay in yards per play defensively, so I don’t think there’s a huge difference between these teams. I’d much rather take the Panthers as home dogs than lay any points with Tampa Bay on Sunday.

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