Mathieu was cut just hours before $5.75 million of his 2018 salary and $8 million of his 2019 salary were to be guaranteed Wednesday afternoon, the first day of the league year. Mathieu was also due a $5 million roster bonus on March 16.
He was asked by the Cardinals to take a pay cut on Thursday but declined.
"I've never made a secret that Tyrann has always had a special place in my heart and always will," Cardinals general manager Steve Keim said in a statement. "While we all understand this is a part of the business, that certainly doesn't make it any easier. We all wish Tyrann nothing but continued success in his career and beyond."
The Cardinals are signing former Cincinnati Bengals offensive tackle Andre Smith to a two-year, $8 million deal that could be worth up to $10.2 million, a source told ESPN's Adam Schefter.
When healthy, Mathieu has been considered one of most dynamic defenders in the NFL. He had a reputation for having a nose for the football and played with a reckless abandon that helped shape who he was as a safety. The 5-foot-9 Mathieu became known as one of the best nickel defenders in the league, preferring to play in the box, where he felt he could make an impact on every play, rather than roaming the secondary.
However, Mathieu's promising career in Arizona was marred by injuries.
Mathieu, 25, finished three of his five seasons on injured reserve thanks to two major knee injuries -- a torn ACL and LCL in 2013 and a torn ACL in 2015. Mathieu's 2015 knee injury derailed the best season of his career. When he went down in Week 15 -- the game the Cardinals clinched their most recent NFC West title -- he was in the conversation for Defensive Player of the Year. He was named a first-team All-Pro and to the Pro Bowl that season.
His 2016 season was cut short by a shoulder injury that landed him on injured reserve.
Last season was the first that Mathieu played in all 16 games as he continued to recover mentally and physically from the past injuries.
He was suspended by LSU before the 2012 season for failing drug tests and then was arrested on drug-related charges that October before leaving school to begin preparing for the NFL draft. He missed the entire 2012 season, leading to him falling to the Cardinals in the third round of the 2013 draft.
In 66 career games, Mathieu has 303 tackles, 25 pass breakups, 22 passes defensed, 11 interceptions, 4 sacks and 4 forced fumbles.
Smith played in 13 games for Cincinnati in 2017 and started eight. His season was cut short in December due to a knee injury, but he said via Twitter on Feb. 2 that he was fully healthy and cleared to play.