Red Sox vs Guardians Prediction, Odds, Moneyline, Spread & Over/Under for Sept. 22

Odds updated as of 6:11 p.m.

The Tuesday schedule in MLB includes a matchup between the Boston Red Sox and the Cleveland Guardians.

Here's what you need to know before checking out today's MLB odds and spreads on FanDuel Sportsbook.

Red Sox vs Guardians Game Info

• Boston Red Sox (84-72) vs. Cleveland Guardians (81-75)
• Date: Tuesday, September 22, 2026
• Time: 6:45 p.m. ET
• Venue: Fenway Park -- Boston, Massachusetts
• Coverage: NESN and CleGuardians.TV

Red Sox vs Guardians Odds & Moneyline

• All MLB odds, betting lines and prop bets are available on FanDuel Sportsbook.
• Moneyline: BOS: (-124) | CLE: (+106)
• Spread: BOS: +1.5 (-220) | CLE: -1.5 (+180)
• Total: 6.5 -- Over: (+104) | Under: (-128)

Red Sox vs Guardians Probable Starting Pitchers

Probable Pitchers: Payton Tolle (Red Sox) - 9-6, 3.02 ERA vs Parker Messick (Guardians) - 12-9, 2.57 ERA

This contest's pitching matchup is set, as the Red Sox will send Payton Tolle (9-6) to the mound, while Parker Messick (12-9) will take the ball for the Guardians. Tolle's team is 10-14-0 against the spread this season in his starts. When Tolle starts a game and his team is the favorite on the moneyline, they have a record of 12-5. The Guardians have gone 16-14-0 against the spread when Messick starts. The Guardians are 5-1 in Messick's six starts this season that they were the moneyline underdog.

Red Sox vs Guardians Prediction & Pick

All MLB win probability predictions and picks are according to numberFire.
Prediction: Red Sox win (56.6%)

Red Sox vs Guardians Moneyline

• Looking at the moneyline for Red Sox-Guardians, Boston is the favorite at -124, and Cleveland is +106 playing on the road.

Red Sox vs Guardians Spread

• The Guardians are 1.5-run favorites against the spread for this matchup with the Red Sox. The Guardians are +180 to cover, while the Red Sox are -220 to cover as a 1.5-run underdog on the runline.

Red Sox vs Guardians Over/Under

• Red Sox versus Guardians on Sept. 22 has an over/under of 6.5 runs, with the odds on the over +104 and the under set at -128.

Bet on Boston Red Sox vs. Cleveland Guardians on FanDuel today!

Red Sox vs Guardians Betting Trends

• The Red Sox have been chosen as favorites in 106 games this year and have walked away with the win 58 times (54.7%) in those games.
• Boston has a record of 45-35 in contests when sportsbooks favor them by -124 or more on the moneyline.
• The Red Sox and their opponents have gone over in 68 of their 153 games with a total set by sportsbooks this season.
• The Red Sox are 72-81-0 against the spread in their 153 games that had a posted line this season.
• The Guardians have been the moneyline underdog 55 total times this season. They've finished 28-27 in those games.
• When playing as a moneyline underdog with odds of +106 or longer, Cleveland has gone 20-18 (52.6%).
• The Guardians have had an over/under set by bookmakers 147 times, and have combined with opponents to go over the total in 73 of those games (73-74-0).
• The Guardians are 70-77-0 ATS this season.

Red Sox Player Leaders

• Wilyer Abreu has 36 doubles, four triples, 24 home runs and 70 walks while hitting .251. He has an on-base percentage of .332 and a slugging percentage of .453.
• He is 77th in batting average, 67th in on-base percentage, and 44th in slugging among all qualified batters in the majors.
• Caleb Durbin is batting .255 with 25 doubles, a triple, 13 home runs and 49 walks, while slugging .389 with an on-base percentage of .338.
• His batting average is 72nd among qualified players, his on-base percentage 57th, and his slugging percentage 100th.
• Durbin heads into this matchup looking to extend his three-game hit streak. In his last five games he is hitting .375 with two doubles and three walks.
• Willson Contreras has 123 hits and an OBP of .387, both of which lead the Red Sox this season.
• Contreras heads into this game with two games in a row with at least one hit. During his last five outings he is hitting .267 with a home run, two walks and two RBIs.
• Jarren Duran has been key for Boston with 110 hits, an OBP of .261 plus a slugging percentage of .362.

Guardians Player Leaders

• Chase DeLauter has racked up 138 hits, a team-best for the Guardians. He's batting .291 and slugging .457 with an on-base percentage of .364.
• Including all qualified hitters, he ranks 10th in batting average, while his on-base percentage is 23rd and he is 38th in slugging.
• DeLauter heads into this game on a three-game hitting streak. During his last five outings he is batting .278 with a home run, four walks and three RBIs.
• Steven Kwan's .378 OBP and .345 slugging percentage are both team-highs. He has a batting average of .280.
• Including all qualified hitters, he ranks 22nd in batting average, 10th in on-base percentage and 129th in slugging percentage.
• Jose Ramirez has 27 doubles, 12 home runs and 58 walks while hitting .237.
• Brayan Rocchio is batting .250 with 24 doubles, two triples, 13 home runs and 37 walks.

Red Sox vs Guardians Head to Head

• 5/31/2026: 9-4 BOS (Favorite: Guardians, Spread: -1.5, Total: 7, Favorite Moneyline: -116, Underdog Moneyline: -102)
• 5/30/2026: 9-1 BOS (Favorite: Guardians, Spread: -1.5, Total: 6.5, Favorite Moneyline: -130, Underdog Moneyline: +110)
• 5/29/2026: 4-3 CLE (Favorite: Guardians, Spread: -1.5, Total: 8, Favorite Moneyline: -124, Underdog Moneyline: +106)
• 9/3/2025: 8-1 CLE (Favorite: Red Sox, Spread: -1.5, Total: 9, Favorite Moneyline: -154, Underdog Moneyline: +130)
• 9/2/2025: 11-7 BOS (Favorite: Red Sox, Spread: -1.5, Total: 7.5, Favorite Moneyline: -270, Underdog Moneyline: +220)
• 9/1/2025: 6-4 BOS (Favorite: Red Sox, Spread: -1.5, Total: 8, Favorite Moneyline: -144, Underdog Moneyline: +122)
• 4/27/2025: 13-3 BOS (Favorite: Red Sox, Spread: -1.5, Total: 7.5, Favorite Moneyline: -118, Underdog Moneyline: -100)
• 4/26/2025: 7-3 BOS (Favorite: Red Sox, Spread: -1.5, Total: 7.5, Favorite Moneyline: -116, Underdog Moneyline: -102)
• 4/26/2025: 5-4 CLE (Favorite: Red Sox, Spread: -1.5, Total: 7.5, Favorite Moneyline: -110, Underdog Moneyline: -106)
• 4/25/2024: 6-4 CLE (Favorite: Guardians, Spread: -1.5, Total: 7.5, Favorite Moneyline: -132, Underdog Moneyline: +112)

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