Smith, a first-team All-Big Ten selection in 2009, applied for a sixth year in November after tearing two knee ligaments in his right knee Sept. 11 against Western Illinois. The season-ending injuries occurred in Purdue's second game.
"The entire Purdue football family is very disappointed for Keith," coach Danny Hope said in a statement. "We're not only losing one of the top wide receivers in the Big Ten, but one of the top leaders on our team. We will do everything we can to help Keith continue his football career and get his Purdue degree."
Smith, who sat out the 2007 season, led the Big Ten in both receptions (91) and receiving yards (1,100) in 2009. He received an invitation to the NFL scouting combine but could not participate in drills as he's still rehabbing from knee surgery.
The NCAA granted a sixth year of eligibility to both Purdue linebacker Jason Werner last season and safety Torri Williams in 2009.
"I just want to say thank you to all of the Purdue fans that have made my college career so much more enjoyable," Smith said in a statement. "I'm disappointed that I won't be in Ross-Ade Stadium playing in front of you on Saturdays, but my time as a Boilermaker has left me with a lot of great memories."
Adam Rittenberg covers Big Ten football for ESPN.com. He can be reached at email@example.com.