Colorado Buffaloes vs Wyoming Cowboys Picks and Predictions September 20th 2025

Colorado’s QB carousel under scrutiny against Wyoming

The Colorado Buffaloes return home Saturday night with quarterback uncertainty dominating the headlines. Deion Sanders’ team sits at 1-2 after a tough loss at Houston, and the offense still hasn’t identified a steady leader under center. They’ll face the Wyoming Cowboys, who travel to Boulder at 2-1 after a humbling defeat against Utah. With both squads searching for answers offensively, this nonconference matchup is pivotal for bettors eyeing college football picks.

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Betting Odds and Trends

The Colorado Buffaloes Can Win If…

The Colorado Buffaloes must find stability at quarterback. Kaidon Salter, Ryan Staub, and freshman Julian Lewis have all seen snaps this season, but no clear leader has emerged. Salter brings mobility—261 passing yards, 67 rushing yards, and two rushing scores—while Staub has shown flashes with 362 passing yards and three touchdowns. If Deion Sanders can identify the right fit for Saturday, Colorado’s offense will flow more consistently.

Running balance will also be essential. Without Shedeur Sanders, the Buffaloes no longer have the same aerial firepower, so establishing the ground game will help take pressure off the quarterback. Utilizing Salter’s dual-threat ability could create mismatches against a Wyoming defense that has bent but not consistently broken this season.

Defensively, Colorado must tighten up. They gave up 36 points to Houston, including costly turnovers that set up short fields. Pressuring Wyoming’s young quarterback Kaden Anderson and forcing him into mistakes could create momentum swings. If Colorado can turn defense into offense with takeaways, they’ll control the pace of this game.

The Wyoming Cowboys Can Win If…

The Wyoming Cowboys need their defense to once again set the tone. Aside from the second-half collapse against Utah, this unit allowed just 10 points over the first 10 quarters of the season. If the Cowboys can replicate that stinginess and frustrate whichever Colorado quarterback starts, they’ll give themselves a chance to win late.

Kaden Anderson must improve his efficiency under center. Against Utah, he completed just 12 of 23 passes for 108 yards with an interception. If Anderson avoids turnovers and makes timely throws, Wyoming can stay within striking distance. Leaning on the run game to chew clock and keep Colorado’s defense on the field will be critical.

Special teams could also factor heavily. With an offense that has only scored 47 points all year—31 of them against an FCS opponent—Wyoming must win the field position battle. A well-timed return or a turnover on special teams could tilt momentum toward the visitors.

The Lean

Oddsmakers list Colorado as a touchdown-plus favorite at -7.5, but the Buffaloes’ shaky quarterback situation makes covering that number risky. Wyoming’s defense has shown it can keep games close, even if its offense has lagged behind. The Cowboys’ ability to limit explosive plays could frustrate Colorado’s rotating quarterbacks.

The total sits at 46.5, and with both offenses struggling for consistency, the under looks like the sharper play. The model projects a 24-17 Colorado victory, meaning the Buffaloes win but Wyoming covers the spread in a low-scoring contest.

Game Preview Recap

Colorado is still searching for answers after Shedeur Sanders’ departure left a massive void at quarterback. Both Staub and Salter have had opportunities, but neither has fully seized the job. Deion Sanders has hinted at his Week 4 choice but has not revealed it publicly, adding to the intrigue.

Wyoming enters licking its wounds after a 31-6 loss to Utah. While the Cowboys’ defense held strong early, their offense failed to capitalize. Coach Jay Sawvel admitted the unit “has to be better” and that urgency will carry into Boulder.

The Cowboys will test Colorado with a physical approach, leaning on their defense to create opportunities. Meanwhile, the Buffaloes will try to lean on playmakers and clean up the turnovers that doomed them in Houston.

This is the first meeting between the programs since 2009, with Colorado holding a 23-3-1 all-time advantage. Both teams come in flawed but competitive, setting the stage for a grind-it-out game under the lights.

Recent Matchups

With both programs looking to steady their footing, this matchup could serve as a turning point. Bettors tracking scores and odds will circle it as a test of whether Colorado can stabilize its offense or if Wyoming’s defense can grind out another upset—lessons also reflected in the NFL betting guide.