The Cavaliers were trying to back up their surprising win over the Los Angeles Lakers on Tuesday and they inched in front by six at halftime against the Pacers.
Indiana then outscored Cleveland by 16 in the third period and rolled on from there to end a two-game skid.
After being held scoreless by Golden State on Dec. 1, George has averaged 24.4 points over his last five outings. That streak included a career-high 34 points against Chicago on Dec. 4.
He produced 27 points Wednesday and grabbed seven rebounds to lead the Pacers, who trailed Cleveland 58-52 at the break. Indiana then dominated the second half 44-23.
David West added 18 points for the Pacers, grabbed nine rebounds and handed out seven assists.
C.J. Miles, who scored 28 points against Los Angeles on Tuesday, had 28 again for the Cavaliers. Miles went 6-of-9 from 3-point range.
Cleveland has lost six out of seven.