Newhouser was a schoolboy star in his hometown of Detroit, Michigan, signed by the hometown Detroit Tigers in 1939 at the age of 18. He went up to the major league club before the end of the season and made his debut on September 29 of that year. In 1940, he earned a spot on the Tigers out of spring training and remained with the team until 1953.

In his first two full big-league seasons, the young left-hander was plagued with control problems, walking more batters than he struck out while posting records of 9-9 and 9-11. He improved in 1942 and 1943, posting excellent ERAs, but still losing more than he won on a team with a weak offense.

As World War II got under way, the Tigers moved up in the standings because several of their top players, including Newhouser, were classified as 4-F (ineligible to the drafted). Newhouser was 4-F due to a leaky heart valve; he attempted to join the service anyway but was turned down several times.

He blossomed all at once in 1944, becoming a dominant pitcher in wartime baseball. That season, Newhouser rang up a 29-9 record while leading the league in wins and strikeouts (187). His 2.22 ERA was second in the league, as were his 25 complete games and six shutouts. Not coincidentally, the Tigers jumped into contention, finishing second in the American League. Newhouser ended the season by being named MVP.

In 1945, he repeated as MVP with what was arguably an even better season. This time, he won the pitcher's Triple Crown, leading the American League in wins (25, against nine losses), ERA (1.81) and strikeouts (212). He also led the league in innings pitched, games started, complete games and shutouts. Newhouser pitched four innings of relief on the season's final day as Detroit rallied for the pennant. He then won two games in the World Series to help his team to the World Championship, including the deciding seventh game.

A year later, many stars came back from the war, and critics predicted that Newhouser wouldn't be as dominant against the "real" major leaguers. But he proved his 1944-45 performance was legitimate by duplicating it in 1946. He went 26-9 with a 1.94 ERA, again leading the league in wins and ERA. He didn't win a third MVP, but he was close, finishing a close second to Ted Williams.

Newhouser continued to rate among the game's best pitchers for the next five years. He won 17 games in 1947, led the AL with 21 wins in 1948 and rung up an 18-11 mark in 1949. After a 15-13 season in 1950, he hurt his arm and his workload was cut significantly.

After being released by the Tigers following the 1953 season, Newhouser signed on with the powerful Cleveland Indians and was their top long reliever in 1954, when Cleveland won the pennant. In his final big-league hurrah, he posted a 7-2 mark with an excellent 2.54 ERA, and got to pitch in his second World Series.

He ended his career with a record of 207-150 and a 3.06 ERA, marks well in line with many baseball Hall of Fame pitchers. In fact, he is the only pitcher ever to win two consecutive MVP awards. But he was passed over for decades because voters discounted his wartime records. But in the late 1980s, the tide turned and more attention was focused on his outstanding record in the five years after the war ended. Finally, in 1992, he was chosen for the National Baseball Hall of Fame .

After retirement, Newhouser worked as a scout for the Houston Astros, Baltimore Orioles and the Tigers. The Tigers retired his number 16 in 1997, and he died a year later following a long illness.