Painter connected on 22 of 37 pass attempts, but was intercepted twice. His main target was Dorien Bryant, who made eight receptions for 82 yards and a touchdown. Kory Sheets added 141 rushing yards and a touchdown on 27 carries.
Purdue (5-0) has won its first five games of the season for just the second time since 1945.
Notre Dame quarterback Jimmy Clausen started for the Fighting Irish (0-5), managing 169 yards on 18 completions in 26 pass attempts. He threw for his first career touchdown before leaving the game with an injury.
Evan Sharpley went in for Clausen and led a come-from-behind effort as he completed 16 of 26 passes for 208 yards, two TDs and an interception for Notre Dame, which is off to its worst start in school history.