The 36-point margin of victory was the largest in the 143-game series between the two schools, and the fourth-worst loss in Southern Illinois history.
The Redbirds (13-10, 4-7 Missouri Valley), who also beat Southern Illinois 70-56 on Jan. 20, made 28 of 35 free throws in Saturday's rematch and limited the Salukis to 30.5 percent shooting.
Desmar Jackson scored 14 points and Anthony Beane Jr. had 10 for Southern Illinois (8-14, 1-10), which has lost six in a row.
Illinois State took control early, building a double-digit lead in the first five minutes.
The Salukis pulled within 52-40 on Beane's 3-pointer with 13 minutes left in the game, but were outscored 31-7 the rest of the way.