Notre Dame said in a statement that there was "evidence that students had submitted papers and homework that had been written for them by others." That evidence was reported to the athletics compliance office on July 29, and an immediate investigation was launched. The NCAA was notified Friday.
The group of players includes KeiVarae Russell, the team's best cornerback, leading returning receiver DaVaris Daniels, and defensive end Ishaq Williams, expected to be a key contributor on the line.
Backup linebacker Kendall Moore is also being held out of practice during the investigation.
All four players were part of Notre Dame's 2012 team, which lost in the BCS national title game to Alabama. Daniels and Russell were starters on that team. Williams was projected to start this year, as well.
Williams and Moore are seniors this season, while Daniels and Russell are juniors. The Fighting Irish are ranked No. 17 in the preseason USA Today/Coaches poll.
A source told ESPN that the four players did not practice Friday.
The Fighting Irish are now facing the possibility that a second straight season could be affected by academic misconduct issues.
Last year, quarterback Everett Golson missed the season after being suspended from school for what he called poor academic judgment. The Irish finished 9-4 behind Tommy Rees, but coming off an appearance in the BCS title game in 2012 it was a step back.
Golson is back, but now coach Brian Kelly could be scrambling to fill holes before opening his fifth season in South Bend at home against Rice on Aug. 30.
Athletic director Jack Swarbrick said Kelly was "devastated" by the news.
The Rev. John Jenkins, the university president, and Swarbrick expressed support for Kelly.
"We have great confidence in Brian and his staff," Jenkins said. "They have been nothing but supportive."
Jenkins said Notre Dame has notified the NCAA about the inquiry. Because of potential violations, the four players can't compete until the conclusion of the investigation and the university honor code process.
Jenkins said during a news conference that no student has been judged responsible for "academic dishonesty."
"Nobody has been dismissed," Jenkins said.
Jenkins would not speculate when asked how far back the misconduct could have taken place.
"Integrity is at the heart of our mission, and academic misconduct will not be tolerated at Notre Dame," Jenkins said. "If the suspected improprieties are proven, we will use the experience to reinforce among our students the importance of honesty in all that they do.
"We are also examining ways of better conveying to students that they can avail themselves of legitimate academic assistance without resorting to cheating."
Jenkins said there is no timetable about how long the investigation will take.
"We will take as long as it takes to have a thorough and fair investigation and proceed through our academic honor code process."
He said such investigations at Notre Dame aren't common "but it happens."
The university also is investigating if other students are involved. Jenkins said it was too early to say if the four players acted together.
Jenkins said if it is found they violated the school's honor code the penalties could range from an F on an assignment, to an F in the course to dismissal from school. The penalty would be decided by an honor committee.
Swarbrick said the players have not been suspended. He said they remain grant-in-aid students and have access to athletic facilities and resources.
Jenkins said evidence students had submitted papers and homework that had been written for them by others was initially detected at the end of the summer session. The case was then referred to the compliance office on July 29.
Jenkins said he didn't want to speculate on possible NCAA punishment, while Swarbrick said the NCAA usually defers to a university when it comes to academic integrity.
"There are a few narrow instances where that triggers an NCAA concern, but I must stress we have no evidence of most of those here. No involvement by a member of the coaching staff, no transcript impropriety, those sorts of things," he said. "If it has NCAA consequences, we'll let them know."
The investigation is the latest in a series for the Irish in the past 15 months involving academics, starting with Golson.
Jerian Grant, the leading scorer on the basketball team at the time, was suspended in December for the spring semester for an academic violation. Daniels was suspended two weeks later for the spring semester and was recently reinstated.
Swarbrick said the previous cases were different.
"Let's not confuse academic probation where you don't make grades in a semester with academic dishonesty. They are very different things," he said.
Jenkins said he believes it shows Notre Dame's honor system is doing its job.
"At any university you're dealing with young people. The vast majority of them make good decisions. But young people sometimes make bad decisions," he said. "Our job is to hold them accountable and to use those incidents as ways to educate them. That's what we're doing."
Information from ESPN.com's Matt Fortuna, Brett McMurphy and Joe Schad and The Associated Press was used in this report.
Notre Dame Investigating Academic Fraud
Joe Schad breaks down the latest on Notre Dame's investigation into academic fraud involving four players on the football team.