Charlotte vs. South Florida Prediction, Odds and Key Players to Watch for College Football Week 6

Betting odds, pick and prediction for the Charlotte 49ers-South Florida Bulls matchup in Week 6 of the college football season.

The South Florida Bulls and quarterback Byrum Brown are favored in Week 6. / Nathan Ray Seebeck-Imagn Images

The South Florida Bulls are coming out of their bye week at 3-1 when they take on the Charlotte 49ers in a Friday night matchup in Week 6 of the college football season.

South Florida opened the campaign with three games in a row against ranked opponents, going 2-1 with its lone loss coming against the Miami Hurricanes. 

In Week 4, South Florida dominated South Carolina State, 63-14, to move to 3-1 in the 2025 season. Now, it takes on a one-win 49ers team that has combined for just 31 total points in its three losses this season.

Oddsmakers have set the Bulls as massive favorites at home in this matchup, but can they cover the spread?

Here’s a breakdown of the odds, players to watch and my prediction for this Week 6 game on Friday night. 

Charlotte vs. South Florida Odds, Spread and Total

Odds via DraftKings Sportsbook

Spread

• Charlotte +26.5 (-102)
• South Florida -26.5 (-118)

Moneyline

• Charlotte: +2000
• South Florida: -6500

Total

• 54.5 (Over -118/Under -102)

Charlotte vs. South Florida How to Watch

• Date: Friday, Oct. 3
• Time: 7:00 p.m. EST
• Venue: Raymond James Stadium
• How to Watch (TV): ESPN2
• Charlotte record: 1-3
• South Florida record: 3-1

Charlotte vs. South Florida Key Player to Watch

Byrum Brown, Quarterback, South Florida

After getting banged up earlier in the season, Brown is expected to play in Week 6 and build on what has been an impressive 2025 campaign.

The Bulls quarterback leads the AAC in yards per attempt and yards per completion, throwing for 983 yards, six touchdowns and two picks while completing 62.9 percent of his passes in four games.

Brown should have a field day against a Charlotte defense that ranks 122nd in the country in defensive success rate and 100th in EPA/Pass. 

Charlotte vs. South Florida State Prediction and Pick

The Bulls have knocked off both Boise State and Florida already this season, beating the Broncos by 27 and the Gators by two. They also are coming off a blowout win against South Carolina State.

I think this is a prime spot to take South Florida to cover the spread at home, as Charlotte has lost three games by double digits and ranks 118th in the country in net EPA/Play. 

South Florida should be better with Brown ready to go off of the bye week, and outside of the loss to Miami, it has held every other opponent this season to less than 20 points. That should help the Bulls win by a wide margin, and it’s worth noting that Charlotte is 100th in EPA/Play on defense despite having a top-50 EPA/Play on offense.

The Bulls have faced much better competition in 2025, and they should be able to build on their 3-1 start on Friday night. 

Pick: South Florida -26.5 (-118 at DraftKings)

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Odds refresh periodically and are subject to change.

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