Ultimately, neither he nor Spanier could withstand the backlash that started when longtime defensive coordinator Jerry Sandusky was charged Saturday with molesting eight boys, and two administrators were accused of covering up one of his assaults.
Paterno and Spanier were not charged, but became targets of relentless criticism that they ignored or failed to act on troubling signs about Sandusky's conduct.
Board of Trustees vice chairman John P. Surma said university provost Rodney Erickson would take over as acting president. Tom Bradley, the football team's defensive coordinator, was named interim head coach.
"These decisions were made after careful deliberations and in the best interest of the university as a whole," Surma said at a late-night news briefing at a hotel following the board's third meeting in four nights.
The news about Paterno drew gasps from the crowd and instantly rippled across the campus, where students gathered in swelling groups.
Thousands took to the streets of downtown State College after the trustees' news briefing. They were met by police in riot gear, who fired tear gas to disperse the crowds. No violence was reported.
Students climbed trees and stood on rooftops along Beaver Avenue, chanting "We want Jo Pa!" and "One more game!" Some carried signs reading "We (heart) Joe Pa."
The drama came at the end of a day when the coach appeared to be fighting to stay through the end of the season - a battle he lost.
"Right now I'm not the coach," Paterno told reporters clustered outside his house late Wednesday. "And I've got to get used to that."
He was in the last year of his contract but had routinely brushed aside questions about if or when he would retire. With an 8-1 record this season, the Nittany Lions seemed poised to earn yet another major bowl appearance - and possibly another year for a head coach who, after 61 years at the school, seemed to never want to leave.
Instead, Paterno was left to share the news of his departure during a tearful, closed-door meeting with players Wednesday.
"It's criminal the way he went out because he's done so much for this university," said offensive tackle Chima Okoli.
Prosecutors said he was not a target in their investigation. Still, Paterno's actions stirred a barrage of questions about what he and other officials knew and did or didn't do.
After two decades as Paterno's defensive coordinator, Sandusky retired from coaching in 1999 to focus on the Second Mile, a foundation he started for underprivileged boys. He maintained an office at the team's complex as an emeritus coach and helped run camps for the boys at the university.
The grand jury report said Sandusky sexually assaulted boys at his home, in the football team's facilities, and during its road trips between the mid-1990s and 2008. It cited eight victims; state police have confirmed that a ninth man had come forward in recent days to say he, too, was abused by Sandusky.
The report said that a graduate assistant saw Sandusky rape a boy in the locker room showers one night in 2002, and reported what he saw to the head coach.
Paterno, according to the grand jury, maintained he was told the incident involved "fondling or something of a sexual nature," but not a sex act, and that he acted appropriately when he referred it to athletic director Tim Curley, and not law enforcement.
Curley and a vice president, Gary Schultz responded by banning Sandusky from bringing boys to the football complex, though Schultz knew police had investigated Sandusky in 1998 for an incident with a boy in a shower, according to the grand jury report.
The administrators allegedly informed administrators at Sandusky's foundation. They also told Spanier, the grand jury report said.
Speaking for the first time about the case, Spanier released a statement Wednesday night saying he "was stunned and outraged to learn that any predatory act might have occurred" on campus or by a campus employee. He added: "I would never hesitate to report a crime if I had any suspicion that one had been committed."
Curley and Schultz are charged with failing to report the 2002 shower incident and then lying to the grand jury about it. Like Sandusky, both have denied any wrongdoing.
Paterno said Sunday that he "did what I was supposed to do," but his resignation statement Wednesday went further. "With the benefit of hindsight," it said, "I wish I had done more."
Gov. Corbett said he was saddened by the developments but also "disappointed in the lack of action" from university officials.
"Let's put it this way: If I saw something like that I would act right away," said Corbett, who as state attorney general led the office managing the Sandusky investigation and now serves on the college's board of trustees. "I think everybody in this room would," he told reporters at a bill signing in Harrisburg.
Corbett said he planned to attend board meetings later this week, and had predicted more action by trustees to restore the school's reputation.
The trustees announced late Tuesday that they would launch their own probe and take steps to prevent similar situations from occurring.
Its special investigation committee will include about 10 board members and a lawyer, and will be formed in coming days, according to a trustee who asked not to be named.
The U.S. Education Department said it would investigate whether Penn State officials violated federal laws that require them to disclose criminal threats on campus.
"Schools and school officials have a legal and moral responsibility to protect children and young people from violence and abuse," Education Secretary Arne Duncan said. U.S. Rep. Patrick Meehan (R., Pa.) had requested the probe.
Spanier spent 25 years at the school. His 16-year tenure as president made him one of the nation's longest-serving university leaders.
Still, that was barely a quarter of Paterno's tenure at Penn State.
In his earlier statement, the coach said he spent his career focused on the best interests of the university and his players.
"My goals now are to keep my commitments to my players and staff and finish the season with dignity and determination," he said. "And then I will spend the rest of my life doing everything I can to help this university."
Hours later, he was fired.
"I am absolutely devastated by the developments in this case. I grieve for the children and their families, and I pray for their comfort and relief.
"I have come to work every day for the last 61 years with one clear goal in mind: To serve the best interests of this university and the young men who have been entrusted to my care. I have the same goal today.
"That's why I have decided to announce my retirement effective at the end of this season. At this moment the Board of Trustees should not spend a single minute discussing my status. They have far more important matters to address. I want to make this as easy for them as I possibly can.
"This is a tragedy. It is one of the great sorrows of my life. With the benefit of hindsight, I wish I had done more.
"My goals now are to keep my commitments to my players and staff and finish the season with dignity and determination. And then I will spend the rest of my life doing everything I can to help this university."
Contact staff writer John P. Martin at 215-854-4774, firstname.lastname@example.org, or @JPMartinInky on Twitter.
Contributing to this article were Inquirer staff writers Angela Couloumbis, Melissa Dribben, Jake Kaplan, Bob Fernandez, Karen Heller, and Jeremy Roebuck.