Wyoming vs. Colorado Prediction, Odds and Key Players to Watch for College Football Week 4

Betting odds, pick and prediction for the Colorado-Wyoming matchup in Week 4.

Colorado Buffaloes head coach Deion Sanders. / Troy Taormina-Imagn Images

Deion Sanders’ Colorado team is just 1-2 in the 2025 season heading into a Week 4 matchup with Wyoming.

The Buffaloes are favored at home in this matchup, but it’s unclear who will draw the start at quarterback after Sanders started former third-string quarterback Ryan Staub against Houston in Week 3. 

Staub played well in Week 2 against Delaware, but it’s possible Sanders could go back to Kaidon Salter after Colorado scored just 20 points in a 16-point loss to the Cougars.

As for Wyoming, it suffered its first loss of the 2025 season in Week 3, scoring just six points against a ranked Utah team. Can the Cowboys pull off a major upset on Saturday night?

Oddsmakers have Colorado favored by double digits in this matchup, but it hasn’t played at a high level so far in 2025.

Here’s a breakdown of the odds, players to watch and my prediction for this Week 4 battle.  

Wyoming vs. Colorado Odds, Spread and Total

Odds via DraftKings Sportsbook

Spread

• Wyoming +13.5 (-115)
• Colorado -13.5 (-105)

Moneyline

• Wyoming: +410
• Colorado: -550

Total

• 44.5 (Over -105/Under -115)

Wyoming vs. Colorado How to Watch

• Date: Saturday, Sept, 20
• Time: 10:15 p.m. EST
• Venue: Folsom Field
• How to Watch (TV): ESPN
• Wyoming record: 2-1
• Colorado record: 1-2

Wyoming vs. Colorado Key Player to Watch

Colorado Quarterbacks

Ryan Staub got the start in Week 3 against Houston, but the Buffaloes lost by 16 points and Staub tossed a pair of picks.

It’s possible that Sanders goes back to Salter, who is a threat on the ground as well as through the air, rushing for two scores in the 2025 season.

Ultimately, the Buffaloes need to find an answer at the position if they want to be taken seriously in the Big 12. Plus, if they’re going to be favored by double digits (like they are in Week 4), there needs to be some consistent player under center for bettors to trust Deion’s club. 

Wyoming vs. Colorado Prediction and Pick

While Colorado should be able to win this game, the lack of clarity at the quarterback position through three games is a major concern. 

The Buffaloes are just 1-2 in the 2025 season, losing to two Power Four opponents in Georgia Tech and Houston. While Colorado did beat Delaware, it did not dominate the game – which is why Staub ended up getting a shot under center.

Wyoming had two wins against Akron and Northern Iowa to open the season, but the team has only scored over 10 points in one game. So, there’s certainly a chance that it struggles to get things going against a Big 12 defense.

Despite that, I’m going to take the Cowboys to cover with this spread nearly set at two touchdowns on Saturday night. 

Colorado is allowing 430 yards per game to opposing offenses, and it’s looked lost at times on offense with Shedeur Sanders now in the NFL. 

Wyoming has also done a solid job against the pass, allowing just 160 yards per game in the 2025 season.

Colorado likely wins this game, but it won’t be a rout. 

Pick: Wyoming +13.5 (-115 at DraftKings)

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Odds refresh periodically and are subject to change.

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