Police said those arrested were caught making "hand-to-hand" sales of marijuana, cocaine, ecstasy and prescription drugs to undercover officers. They said the bust followed a six-month investigation prompted by complaints from students, parents and others.
"There is no doubt," TCU Police Chief Steve McGee said at a morning news conference.
Police said they had not determined whether any of the players were selling to other athletes. Chancellor Victor Boschini suggested the four players' involvement was not a sign of a larger issue.
"I don't think it's a football problem," Boschini said.
Still, the arrests stunned the campus community, coming just one day after a thrilling overtime victory by the men's basketball team and less than 24 hours after TCU released its football schedule for next season, its first in the Big 12 Conference. TCU has an enrollment of about 9,500 students.
"There are days people want to be a head football coach, but today is not one of those days," coach Gary Patterson said. "As I heard the news this morning, I was first shocked, then hurt and now I'm mad."
Three key defensive players on the team were arrested: Linebacker Tanner Brock, the leading tackler two seasons ago, defensive tackle D.J. Yendrey and cornerback Devin Johnson. The other player is offensive lineman Ty Horn.
Officials said the students had been "separated from TCU," but it wasn't clear if the players had been kicked off the team.
"I expect our student-athletes to serve as ambassadors for the university and will not tolerate behavior that reflects poorly on TCU, the athletics department, our teams or other student-athletes within the department," athletic director Chris Del Conte said. "Our student-athletes are a microcosm of society and unfortunately that means some of our players reflect a culture that glorifies drugs and drug use. That mindset is not reflected by TCU nor will it be allowed within athletics."
Brock was the leading tackler for TCU as a sophomore during the 2010 season, when the Horned Frogs went 13-0, won the Rose Bowl and finished the year ranked No. 2. Brock started the season opener at Baylor last September, but aggravated a foot injury that required season-ending surgery.
As a freshman playing special teams against SMU in 2009, Brock gained some national attention with a highlight play. He lost his helmet and still threw a key block on a 71-yard punt return for a touchdown by Jeremy Kerley.
Yendrey started 12 of 13 games this past season, when he had 39 tackles and three sacks. Johnson played in all 13 games, starting the last eight, and had 47 tackles with 2 1/2 sacks.
Brock likely would have been a starter again in 2012. Yendrey, who also started five guys as a junior, and Johnson both were juniors last season and had another season of eligibility. Horn appeared in 10 games this past season, making one start. He played in eight games as a freshman.
"Under my watch, drugs and drug use by TCU's student-athletes will not be tolerated by me or any member of my coaching staff," Patterson said. "Our program is respected nationally for its strong ethics and for that reason the players arrested today were separated from TCU by the university. I believe strongly that young people's lives are more important than wins or losses.
He added: "At the end of the day, though, sometimes young people make poor choices. The Horned Frogs are bigger and stronger than those involved."
The move to the Big 12 is expected to be a boon for the athletic program, which has been bolstered by the strong performance of the football team the past several years. Last season, the Frogs finished ranked No. 14 following their third consecutive Mountain West Conference title and fourth straight year with at least 10 wins. TCU is scheduled to play in the first Big 12 game of the season, Sept. 15 at Kansas.
AP Sports Writer Stephen Hawkins contributed to this report.