Spanier's ouster was announced Wednesday by university trustees. One of the nation's highest-paid college presidents, he had come under fire over the past several days for his handling of allegations that a former assistant football coach sexually abused boys on campus.
The scandal also claimed longtime football coach Joe Paterno, who had announced Wednesday that this would be his last season in Happy Valley but wasn't given the chance to continue coaching, and two other top administrators, who stepped down earlier this week after being charged with perjury in the case.
Former assistant football coach Jerry Sandusky was charged last week with molesting eight boys over a 15-year period. He has denied the charges.
A grand jury report said at least two of the assaults were witnessed on campus - and one of those was reported to Spanier.
But the university president did not tell authorities about the reported attack on a young boy, which a football team graduate assistant claimed to have seen in 2002. The graduate student's accusation was passed up the chain of command to Spanier, but he said the seriousness of the encounter was not conveyed to him.
The investigation is continuing. State Attorney General Linda Kelly said Monday that Paterno is not a target of the inquiry into how the school handled the matter, but she refused to say the same for Spanier.
State police Commissioner Frank Noonan earlier this week criticized school officials' handling of the allegations, saying "a football coach or a university president or the guy sweeping the building" had a moral responsibility to call police if they suspected a child was being sexually abused. He also said Penn State had "a culture that did nothing to stop it or prevent it from happening to others."
Calls for Spanier's ouster by newspapers, online groups and petitions mushroomed in recent days, many supported by upset and disillusioned alumni.
The 63-year-old Spanier has led Penn State since 1995, and his current contract runs through 2015. The mammoth university system headquartered in State College includes 96,000 students on 24 campuses and has an annual budget of about $4.3 billion.
Spanier is among the highest-paid public college presidents in the country, earning more than $800,500 in annual base pay, deferred compensation and retirement contributions, according to The Chronicle of Higher Education.
He told The Associated Press earlier this year that he considered his salary, which was set by trustees, to be "very generous" and that it "feels peculiar for someone who grew up in a poor family."
Spanier has donated more than $1 million to the university. He also has overseen $3 billion in philanthropic contributions to Penn State during his tenure, according to his biography.
Spanier is well known in academics and athletics, both inside and outside Pennsylvania. He heads the Bowl Championship Series presidential oversight committee, hosts a sports talk show on the Big Ten's television network and previously led the Association of Public and Land-grant Universities.
Penn State is a state-related institution that receives some public funding but is not under direct state control.
Spanier is trained as a family sociologist, demographer and marriage and family therapist. He first served in Happy Valley from 1973 to 1982 as a member of the faculty and in three administrative positions in the College of Health and Human Development.
He later went on to serve as chancellor of the University of Nebraska-Lincoln, provost and vice president for academic affairs at Oregon State University and vice provost for undergraduate studies at the State University of New York at Stony Brook.
He received bachelor's and master's degrees from Iowa State University, followed by a doctorate in sociology from Northwestern University.
Spanier and his wife, an English professor at the university, have two children, both Penn State graduates.
Penn State student body President T.J. Bard, who said he has worked closely with Spanier over the past two years, called the president "a phenomenal leader for this university."
"That's not something that should be overlooked very quickly," he said.
Associated Press writers Kathy Matheson and Patrick Walters in Philadelphia contributed to this report.