Mason had a 27-55 record in his sixth season at Vanderbilt. He is the sixth-winningest coach in program history and only the second to lead the Commodores to two bowl games.
In a statement on Twitter, Mason wrote, "It has truly been my honor to have been given the opportunity to teach, mentor, champion and coach hundreds of Vanderbilt young men and one courageous female."
"On behalf of the entire Vanderbilt community, I want to extend my deepest gratitude to Coach Mason for his many years of dedication and service leading our football program," athletic director Candice Storey Lee said in a statement. "Derek cares deeply about the student-athletes under his charge. His tenure at Vanderbilt will be remembered for his steadfast commitment to our student-athletes, not only on the field, but in the classroom and as young people."
Offensive coordinator Todd Fitch will serve as interim coach. Vanderbilt said the search for a new coach will begin immediately.
Vanderbilt plays at No. 9 Georgia on Saturday and is working to reschedule its final home game against Tennessee, which was postponed by the SEC to help Missouri catch up on games played. The Commodores have never had a winless campaign in their 117-year history.
Despite competing against SEC programs with far greater resources and recruiting bases, Mason guided the Commodores to at least five victories in three straight seasons from 2016 to 2018. He became the first Vanderbilt coach since the 1920s to beat in-state rival Tennessee three straight seasons, and his teams played in the 2016 Independence Bowl and 2018 Texas Bowl.
Vanderbilt went 3-17 the past two seasons combined, however, including 1-15 in the SEC. The Commodores have lost 12 straight SEC games, the longest active streak for a Power 5 school.
At least seven Vanderbilt players opted out of the 2020 season, with eight others transferring. Linebacker Dmitri Moore opted out and then changed his mind before deciding to transfer after playing in a loss to then-No. 6 Florida.
Among the candidates who might be targeted by Vanderbilt are former Tennessee Titans coach Jeff Fisher, Buffalo's Lance Leipold, Notre Dame defensive coordinator Clark Lea (a former Vanderbilt fullback), Princeton's Bob Surace, Nevada's Jay Norvell, Indiana's Tom Allen, Tulane's Willie Fritz, Clemson offensive coordinator Tony Elliott, Louisiana Tech's Skip Holtz, Charlotte's Will Healy, Coastal Carolina's Jamey Chadwell, Army's Jeff Monken, Navy's Ken Niumatalolo and North Dakota State's Matt Entz.
ESPN's Adam Rittenberg and The Associated Press contributed to this report.