Maglie broke into the major leagues with the Giants in 1945, but jumped to the Mexican League prior to the 1946 season. For this, Maglie was banned from organized baseball by Commissioner Happy Chandler, and Maglie was unable to return to the Giants until 1950. The ban had been lifted in 1949, but Maglie chose to remain with the Drummondville Cubs, with whom he was playing at the time, and for whom he was making more money than he did with the Giants.

After his return, Maglie was integral to the success of the New York Giant teams of the early 1950s. After a stint with Cleveland, Maglie was purchased by the Dodgers in May 1956. Maglie had a sterling comeback season for the Brooklyn Dodgers in 1956 (who won the NL pennant by one game over Milwaukee and two games over Cincinnati), going 13-5 with 2.89 ERA, tossing a no-hitter on September 25. He finished second to Don Newcombe in the first balloting for the Cy Young Award, and was also second to Newcombe in MVP balloting. He was the Dodgers' pitcher opposing Don Larsen of the Yankees in the latter's famous perfect game of the 1956 World Series.

After two terms (1960-62; 1966-67) as pitching coach of the Boston Red Sox, Maglie took a similar post for the expansion Seattle Pilots in 1969. He was profiled unflatteringly in Jim Bouton's book Ball Four, despite the fact that he was a boyhood hero of Bouton. Bouton commented that Maglie rarely gave useful advice to the pitchers, and frequently second-guessed their choice of pitches, often contradicting his previous second guessing.

However, Hall of Fame pitcher Don Drysdale credited Maglie with teaching him to pitch inside, for which he would be noted. Jim Lonborg, AL Cy Young Award winner in 1967 also learned to brush hitters back under instruction from Maglie.[citation needed]

The book Carl Erskine's Tales from the Dodgers Dugout: Extra Innings (2004) includes short stories from former Dodger pitcher Carl Erskine. Maglie is prominent in many of these stories.

During the 1950s, Maglie lived in Riverdale, The Bronx.

The Sal Maglie Stadium, located in Hyde Park in his hometown of Niagara Falls, New York, is named for him. It is home to the Niagara Purple Eagles college baseball team, Niagara Catholic Patriots (high school baseball), and Niagara Power of the NYCBL.

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