Mike Mayers attended Grove City High School in Grove City, Ohio, and played college baseball for the Ole Miss Rebels of the University of Mississippi.  On May 13, 2013, he was selected as a Southeastern Conference Co-Pitcher of the Week. In his junior year, he posted a 2.83 earned run average (ERA) over 921⁄ 3 innings pitched (IP) with 73 strikeouts (SO) and 37 bases on balls (BB). Overall, in his college career, he posted a 12−9 win–loss record (W−L) with a 3.42 ERA and 171 strikeouts in 215 innings. He decided to forgo one remaining year of eligibility and avail himself to the Major League Baseball draft. 
The St. Louis Cardinals selected Mayers in the third round of the 2013 amateur draft.  In 2015, Mayers underwent surgery for thoracic outlet syndrome (TOS).  Recovered from TOS, Mayers progressed through the two highest minor league levels in 2016. First, he pitched for the AA Springfield Cardinals in the Texas League,  where he was selected a mid-season All-Star.  Over nine starts for Springfield, Mayers was credited with a 5−2 W−L and 2.30 ERA. After promotion to the AAA Memphis Redbirds of the Pacific Coast League (PCL), he made nine starts and was 3−3 W−L with a 2.94 ERA. 
The Cardinals selected Mayers' contract from Memphis on July 23, 2016, and announced that he would make his Major League Baseball (MLB) debut the following day against the Los Angeles Dodgers on national television on ESPN's Sunday Night Baseball.  In his debut, each of the first four batters he faced in the first inning reached base, and all scored on a grand slam to the fourth, first baseman Adrian Gonzalez.  In all, 10 of 14 batters reached base as Mayers surrendered nine earned runs, eight hits and two walks, while recording four outs for an in-game ERA of 60.75. Per the Elias Sports Bureau, he became the first major leaguer to surrender at least nine runs while advancing through fewer than two innings in his debut.  Said opposing starter Scott Kazmir of Mayers, "I felt for him, yeah. It's your debut, it's hot and it's on ESPN. It was a tough draw for him."  The Cardinals optioned him back to Memphis the day after his first major league start. 
He got his first win, in relief on September 6, in Pittsburgh, pitching a perfect eighth inning.