O'Brien, a former assistant coach for the New England Patriots, will return to the NFL as head coach of the Houston Texans, university athletic director Dave Joyner said at a campus press conference in State College, Pennsylvania.
"Bill O'Brien has informed Penn State that he is resigning from his position as head coach of the football program to become head coach in the National Football League for the Houston Texans," Joyner said.
"A national search will begin immediately to select Penn State's 16th head football coach," he said. "I just want to emphasize that we are happy for Coach O'Brien."
O'Brien was not at the press conference, and the Houston Texans have not made any announcement on a new coach.
O'Brien was hired in January of 2012 in the wake of a criminal case against former Penn State assistant football coach Jerry Sandusky, who was ultimately convicted on 45 charges of child sex abuse.
As a result of the scandal, Paterno, the winningest coach in college football history, and Sandusky's boss, was fired in 2011. Paterno died of lung cancer in January of 2012, when O'Brien was hired.
O'Brien compiled a 15-9 record in his two seasons coaching Penn State's Nittany Lions, a feat made more difficult by sanctions the NCAA placed on the football program as a result of the Sandusky scandal. Sanctions included limiting the number of scholarships the school could offer football players, a $60 million fine, forfeiting wins from 1998 to 2011, and a ban on post-season bowl appearances.
In the NFL, the Texans finished the year with a 2-14 record.
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- Dave Joyner