Lee was born in Sonoma, California. Something of a later bloomer, he didn't pitch professionally until he was 24. He finally reached the major leagues on September 19, 1933, just six days after his 28th birthday, with the Cleveland Indians.

From the beginning, Lee had a tough time earning respect, even though he had success at almost level of the game. He showed a fine sinking fastball, a good control, was effective holding runners and fielding, and produced with the bat as well. Before the 1937 season, he was part of a three-team trade between the Indians, Chicago White Sox and Washington Senators. Jack Salveson went to the Senators, while Earl Whitehill went to the Indians. Lee landed in Chicago and went on to pitch for the White Sox for the next 11 years.

In his first four years with the Sox, Lee won 12 or more games, with a high 15 victories in 1939, despite a little offensive support left him on the losing end of many close decisions. His most productive season came in 1941, when he paced all American League pitchers in ERA (2.34) and complete games (30). He also posted a career-high 22 victories (second only to Bob Feller's 25), 125 strikeouts (also a career-high), was named to the AL All-Star team, and collected a $2,500 bonus for winning more than 20 games.

From 1942-45, Lee suffered a string of injuries and lost his pace. After breaking his arm and undergoing two bone chip removals and a neck operation, he recovered his old form in 1945, going 15-12 with a career-high 2.44 ERA and 108 strikeouts, and pitching in the All-Star game for second time.

At the age of 42, Lee divided his time in 1948 between the National League, with the Giants, and the Pacific Coast League, where he contributed to the Oakland Oaks pennant championship. He retired at the end of the season.

Thornton Lee died in Tucson, Arizona, at 90 of age.