Khyle Marshall added 18 points for Butler (13-16, 3-14 Big East) as the Bulldogs put an end to a season-high seven-game losing streak.
Brandon Young led DePaul (11-20, 3-15) with 24 points. The Blue Demons will end the Big East regular season with at least a share of last place for the sixth straight season.
DePaul finished 1 of 18 from 3-point range. Despite a game featuring the conference's bottom two teams, Butler dominated DePaul in every aspect. The Bulldogs opened the game with an 18-4 lead. Barlow scored eight points in the span and Marshall drove the lane for two uncontested dunks.
Butler outrebounded DePaul 46-29 for the game.
DePaul was held to a season-low scoring output in losing by its largest margin this season.
Butler ended the first half with Nolan Berry's dunk with 3 seconds left followed by Barlow stealing the inbounds pass and scoring on a 3-pointer as time expired to take a 38-18 lead.
Barlow, who came in the game averaging 6.2 points, eclipsed his career high in the opening minutes of the second half with a 3-pointer and a jumper to give him 16 points for his career-high. Kellen Dunham made a 3 and Marshall's basket gave Butler a 53-20 lead with 15:31 left.
Butler rebounded from a season-low shooting performance in a road loss to Villanova on Feb. 26.
DePaul was outrebounded 26-12 in the first half and shot just 28 percent.
Barlow scored 13 points on 5-of-6 shooting in the half for Butler and Marshall added nine.
DePaul had its lowest scoring output in the first half this season with 18 points, Young scoring 10 of those.
Before the game, Young was honored along with Sandi Marcius and Edwind McGhee. The three seniors played in their last home game.
DePaul has lost 12 of its last 13 games.
Dunham finished with six points and nine rebounds.