Also known as "Black Mike," Cochrane was educated at Boston University where he played five sports. He broke in with the Philadelphia Athletics in 1925 as the team's starting catcher, quickly establishing himself as one of the best offensive players ever at the position. A left-handed batter, Cochrane ran well enough that manager Connie Mack would occasionally insert him into the leadoff spot in the batting order. Most frequently, Cochrane would bat third, but wherever he hit, his primary job was to get on base so that hard-hitting Al Simmons and Jimmie Foxx could drive him in.

Known for his fiery temper, Cochrane and teammate Lefty Grove were known to tear up locker rooms after difficult losses. Cochrane was a close friend of fellow baseball legend Ty Cobb. Cobb was a good friend to him, helping Cochrane out financially, at the end of his life. Mickey Cochrane (along with Ray Schalk) would be the only friend to attend Cobb's funeral.

Cochrane enjoyed his best year in 1930, when he hit .357 with 10 home runs and 85 RBI and scored 110 runs. He played in three World Series with the Athletics, and was blamed by many for the loss of the 1931 World Series against the St. Louis Cardinals who, led by Pepper Martin, stole eight bases in the series, five of those by Martin.

In 1934, Connie Mack started to disassemble his dynasty for financial reasons and sold Cochrane to the Detroit Tigers, who made him player-manager. Cochrane led the Tigers to the World Series in 1934 and 1935.

Cochrane's playing career came to a sudden end on May 25, 1937 when he was hit in the head by a pitch by Yankees pitcher Bump Hadley. Hospitalized for seven days, the injury nearly killed him. Ordered by doctors not to play baseball again (he was just 34 years old), Cochrane returned to the dugout but had lost his competitive fire. He managed for the remainder of the 1937 season and was replaced midway through the 1938 season. Cochrane's all-time managerial record was 348-250, for a .582 winning percentage.

Despite his head injury, Cochrane served in the United States Navy during World War II, as did Bill Dickey of the Yankees, giving the Navy the two greatest catchers baseball had yet seen; with Yogi Berra also serving but not yet having reached the major leagues, there were actually three possible "greatest catchers ever" in the WWII-era Navy.

Cochrane was elected into the Baseball Hall of Fame in 1947. He died in 1962 in Lake Forest, Illinois of lymphatic cancer, at the age of 59.

With the Athletics having moved out of Philadelphia in 1954, and never retiring the uniform number 2 he wore with them, the Philadelphia Phillies honored Cochrane by elected him to the Philadelphia Baseball Wall of Fame at Veterans Stadium. The Athletics' plaques from that display have been moved to the Philadelphia Athletics Museum in Hatboro, Pennsylvania. The Tigers honored him by renaming National Avenue, behind the third-base stands at Tiger Stadium, Cochrane Avenue, but have never retired the uniform number 3 he wore with them.

In 1999, he ranked number 65 on The Sporting News' list of the 100 Greatest Baseball Players, and was a nominee for the Major League Baseball All-Century Team.