Arizona coach Bruce Arians on Monday confirmed Mathieu tore an ACL and sustained further damage in his left knee and will undergo surgery.
Mathieu, who earned the nickname "Honey Badger" in his days at LSU, was Arizona's starting safety and had been in on almost every defensive play for the Cardinals.
He was injured returning a free kick after John Abraham had tackled Kellen Clemens in the end zone in the third quarter of Arizona's 30-10 victory over St. Louis on Sunday.
After Mathieu was buried in a pile of tacklers, he tried to jog off the field but his knee buckled and he collapsed. Mathieu blew a kiss to the crowd as he was carted off.
"I appreciate everyone prayers," he said in a tweet on Sunday. "We go through things in life to test our faith & strength."
Arians indicated the injury was extensive and said he doubts Mathieu would be ready for training camp next year. The surgery probably will happen next week and the recovery period will be "a long one," the coach said .
"He'll have some ACL and LCL repair and too many other L's for me to get into," Arians said. "It's a shame."
Mathieu was considered a risk when the Cardinals selected him in the third round of this year's draft. A Heisman Trophy finalist at LSU in 2011, he was dismissed from the team and kicked out of school for marijuana-related issues and was out of football in 2012.
But the 5-foot-9 dynamo was a great addition to the Arizona squad and nearly impossible keep off the field.
"He's been fantastic and he's a leader," Arians said. "Very seldom do you see young guys come in and become a leader, especially in the secondary like he has. His personality is infectious with the guys because he loves football. He'll stay out there and practice all day and go as hard as he can. Those are guys you miss."
Rashad Johnson will return to the safety spot.
Arians said Mathieu cried when the two talked.
"He was sad. He's never been injured. These guys that get hurt for the first time, it's devastating," Arians said. "When you take away the thing he loves the most and works so hard for, he was devastated. But he'll get over it. He's strong. He's got a lot of support."
In his first game, he chased down St. Louis' Jared Cook and knocked the ball out of the tight end's hands just before the Rams receiver reached the goal line.
Mathieu, a starter from the second week of the season, has the second-most total tackles on the team with 63 and second-most solo tackles at 56. He had one sack, one interception, one forced fumble and 15 passes defensed.
"I still think he should get rookie of the year defensively," Arians said. "The job he did in the three positions that he played (safety, nickel back and cornerback). I don't know if it will hurt him where somebody else will get it, but he meant a lot to us because of his flexibility and his positions. It will take two guys to take his place."
Close friend and teammate Patrick Peterson tweeted his support.
"Man I just want to wish my boy @Mathieu_Era for a speedy recovery," Peterson wrote. "Hurt me to my heart to see a King go down like that."
More Sports Headlines
Seahawks escape with 13-10 victory over winless Lions Lions force Seahawks' Wilson to run for his life Seahawks' defense benefits from missed call Seahawks cornerback Williams plays his best game against Lions Seahawks report card Seahawks improve to 22-8 on MNF Huskies' Petersen thinks Trojans are underrated? Rams linebacker Ogletree to have surgery for broken right ankle
Our new comment system is not supported in IE 7. Please upgrade your browser here.