Picked up by the Red Sox the next year, despite his impressive hitting in Seattle (.301 average), it was soon clear that he needed to spend some time lower in the minor leagues to learn to catch.

After the 1950 season, White decided to try professional basketball also and tried out with the Minneapolis Lakers of the NBA, where he made it to the final cut.

He made his major league debut with the Red Sox in September 1951. The Sox used seven different players at catcher, and manager Lou Boudreau finally selected him to provide some stability behind the plate in 1952.

White first became a Boston fan favorite during an 11-9 victory over the St. Louis Browns when he hit a game-winning grand slam. As the season progressed his strong play continued and he placed third with seven votes for "Rookie of the Year". The Boston Baseball Writers Association voted him as their co-"Rookie of the Year", along with Eddie Mathews of the Boston Braves.

In 1953, White picked up right where he had left off. He demonstrated that he had improved at the plate in handling the pitching staff. That season he started almost every Red Sox game.

In June he earned a permanent place in the baseball record books during a 23-3 Red Sox shellacking of the Detroit Tigers. The Sox scored 17 runs against the Tigers in the seventh inning, and White became the first 20th-century player to score three runs in one inning. His outstanding first-half play earned him an invitation to the All-Star Game in Cincinnati, and after three full seasons as the regular Red Sox catcher, he was acknowledged as one of the premier catchers in major league baseball.

In 1955, he was behind the plate for nearly every game, but catching nearly every day took its toll on his offensive production. His batting average fell to .261 from .282 the previous season.

As the season wore on in 1956, his back began to bother him and his hitting continued to suffer. His batting average fell to .245 and he ended up split playing time with Pete Daley during the second half of the year. The following season, his batting average dropped to .215

Little changed for the Red Sox in 1958, but White did show signs of regaining his batting stroke and his offense continued to improve in 1959. In what would turn out to be their last year as teammates, he outhit Ted Williams by 30 points, finishing with a batting average of .284

White was the last Red Sox player to sign his 1960 contract. His business venture, "Sammy White’s Brighton Bowl" saw him very involved in the bowling alley all the way through, from the construction to the operation.

In March, White was traded to the Cleveland Indians for catcher Russ Nixon. He promptly announced his retirement from baseball, sitting out the 1960 season to focus on his bowling enterprise. But in 1961, the Milwaukee Braves coaxed him out of retirement and he was the backup to Joe Torre.

After retirement from baseball, White rejoined his friend and former batterymate Frank Sullivan on Kauai in Hawaii. The pair originally worked in construction but became certified as golf professionals by the PGA in 1978. Sammy White became the director of golf for the Princeville Resort on Kauai, where he worked until he died in 1991.