Chiefs vs. Chargers Final Score Prediction for NFL Week 1 (Can Mahomes Dominate an AFC West Foe?)

The second game of the 2025 NFL season is set for Friday night in San Paolo, Brazil as the Kansas City Chiefs will take on Justin Herbert and the Los Angeles Chargers.

Both of these teams made the playoffs in the 2024 season, but the Chiefs made it all the way to the Super Bowl while Herbert tossed a bunch of picks in a loss to the Houston Texans. Still, neither squad came away with the Lombardi Trophy, as the Philadelphia Eagles blew Mahomes and the Chiefs out in the Super Bowl.

But, that’s the beauty of a new season. Expectations are sky high, and everyone has a clean slate.

In Week 1, the Chiefs are set as favorites at the best betting sites, but they struggled against the spread at the end of the 2024 season.

All season long, we’re going to share score predictions here at SI Betting, using the latest odds and analysis to attempt to get a score right – and give bettors our thoughts on both the spread and total.

Here’s where I’m leaning for Friday night’s standalone matchup between two AFC West contenders.

Chiefs vs. Chargers Odds, Spread and Total

Odds via DraftKings Sportsbook

Spread

Chiefs -3 (-115)
Chargers +3 (-105)

Moneyline

Chiefs: -170
Chargers: +142

Total

45.5 (Over -110/Under -110)

Kansas City has won seven games in a row against the Chargers, and Mahomes has been elite against the AFC West in his career, going 35-5 in 40 games.

Still, Kansas City has covered just four times in its last 14 games, so bettors need more from Mahomes and company to cash a spread pick with this game sitting at the key number of three.

Chiefs vs. Chargers Final Score Prediction

Earlier this week, SI’s NFL betting insider Iain MacMillan shared his thoughts on this game in his Road 272 column, where he bets on every NFL game, every week throughout the 2025 season:

People are writing off the Chiefs this season. Picking them to snap their nine-year streak of winning the AFC West and taking a huge step back. I know their Super Bowl loss is fresh in everyone's mind, but let's remember this team went 15-2 last year. Even as someone who was a detractor of theirs last season, underestimating the Patrick Mahomes and Andy Reid combination is a dangerous game to play.

Let's not crown the Chargers quite yet. They still have plenty of questions. They have a rookie at running back, one of their starting tackles, Rashawn Slater, is out for the season, and they're still trying to figure out who their No. 2 receiver is. The fact of the matter is, the Chiefs are the more experienced team and are confident in their identity. On a neutral field, I think the Chiefs deserve to be bigger favorites than they are. I'll lay the field goal.

I agree with MacMillan’s assessment of the Chargers, as losing Slater could be a huge blow to the team’s offensive attack.

Kansas City wasn’t great against the number in 2024, but I do think it wins this game since Mahomes has dominated division opponents year after year since becoming the team’s starter.

With the total sitting at 45.5 and the Chargers using a run-heavy offense in 2024, I think this game goes under the total, but KC ends up on top.

Final Score Prediction: Chiefs 20, Chargers 17

Odds refresh periodically and are subject to change.

If you or someone you know has a gambling problem and wants help, call 1-800-GAMBLER.

Claim the latest DraftKings promo code offer today. Sign up and place a $5 bet to earn a guaranteed $200 in bonus bets plus over $200 off NFL Sunday Ticket. Regardless of the outcome of your wager,DraftKings will add eight $25 bonus bet tokens to your new account and award one promo code for a discounted NFL Sunday ticket subscription.