Mize was born in Demorest, Georgia to Edward and Emma Mize. After his parents separated, his mother went to Atlanta for work, but Mize remained in Demorest with his grandmother. He later played baseball for Piedmont College. Mize was a distant cousin of Ty Cobb and his second cousin married Babe Ruth.
Mize was known as both "Big Jawn" and "The Big Cat" for his smooth fielding at first base. He had a fine batting eye, and in his early career hit for high averages, leading the National League with a .349 batting average in 1939. Mize came up through the St. Louis Cardinals minor league system but was traded to the Cincinnati Reds in 1934. However, Mize suffered a groin injury and the Reds nullified the trade. Mize then spent two more years in the minors before making his Major League debut for the Cardinals in 1936.
In 1938 he batted .363, but Cardinals teammate Joe Medwick took the title with a .374 average. Mize then changed targets and went for power instead of batting average. He led the National League in home runs in 1939 with 28, and in 1940 with 43, also leading the league in runs batted in twice, in 1940 and 1942. At the end of the 1941 season, however, he was traded to the New York Giants by Cardinals general manager Branch Rickey, who famously believed in trading players before their skills began to decline.
In 1941, Mize was involved in a lawsuit against Gum Products Inc. The company manufactured a set of baseball cards called Double Play. Mize sued because he argued that the company did not have his consent to use his image in the card set.
Mize spent 1943 through 1945 in military service during World War II. Returning to the Giants in 1946, a broken toe caused him to fall one short of the home run title, won by Ralph Kiner of the Pittsburgh Pirates. In 1947 he rebounded to hit 51 home runs and tie Kiner for the league lead. He also led in runs and RBI, and became the only player to strike out fewer than fifty times while hitting fifty home runs. This combination of power and control was a mark of Mize's style; he also had seasons of 43 home runs and 49 strikeouts, and of 40 home runs and 37 strikeouts. In 1948, Mize and Kiner again tied for the league home run championship with 40 each. Mize was traded to the New York Yankees late in the 1949 season after expressing discontent with his playing time.
Mize spent the last five years of his career with the Yankees, mostly as a part-time player, ending in 1953. He was, however, considered a valuable contributor to their winning an unprecedented five consecutive American League pennants and World Series titles. He hit 25 home runs in 1950 (despite spending part of the season on minor league rehab) to become the second player, joining Hank Greenberg three years earlier, to have a 25-home run season in both leagues. In the 1952 World Series against the Brooklyn Dodgers, he hit three home runs, one as a pinch-hitter, and was robbed of a fourth by Dodger right fielder Carl Furillo, who made a leaping catch above the fence in the 11th inning to preserve a win for the Dodgers.
Mize during his time with the Yankees.
Mize holds the Major League record for the most times hitting three homers in one game, a feat he performed six times. He also was one of a handful of players (including Babe Ruth) to do it in both leagues — five times in the National League and once in the American. He was the first player to hit three home runs in a game twice in one season in 1938 and did it twice again in 1940. He finished his career with 359 home runs. Like Joe DiMaggio, Ted Williams, and Hank Greenberg, all of whom spent at least three years in the military at the peak of their power, Mize undoubtedly lost a large number of home runs because of his service. His 43 home runs in 1940 broke the Cardinal record of 42 set by Rogers Hornsby in 1922 – and remained the record until Mark McGwire hit 70 in 1998. Mize still holds Cardinal records for most home runs in a season by a left-handed batter, most season RBIs by a left hander, and most games with three or more home runs. He and Carl Yastrzemski are the only players to have three seasons of hitting 40 or more home runs, without a season of hitting between 30 to 39 home runs.
In the 1970s, Mize made his home in St. Augustine, Florida, working for a development by the Deltona Corporation called St. Augustine Shores. A picture of his house is included in David Nolan's book The Houses of St. Augustine.