[16] The Red Sox promoted Benintendi to the major leagues on August 2, 2016, straight from Double-A, only 421 days after being selected in the draft.

Benintendi ended the 2016 season with a .295 batting average, 31 hits, 14 RBIs, two home runs, and one stolen base in 34 games played.

[21] Benintendi started the 2017 season as part of the Red Sox' Opening Day roster, batting second as Boston defeated the Pittsburgh Pirates by a score of 5–3.

[25] Overall, during the 2017 Red Sox regular season, Benintendi batted .271 with 20 home runs, 90 RBIs and 20 stolen bases in 151 games played.

[26] In the ALDS against the eventual World Series champions, the Houston Astros, he batted .250 (4-for-16) with a home run and two RBIs in four games.

[30] The Red Sox won the World Series over the Los Angeles Dodgers, giving Benintendi his first championship title.

[37] On February 8, 2020, the Red Sox announced signing Benintendi to a two-year contract worth $10 million, avoiding arbitration.

[38] On July 29, he recorded the 500th hit of his major league career, a ground rule double off of New York Mets pitcher Jeurys Familia.

[42] On February 10, 2021, the Red Sox traded Benintendi and cash considerations to the Kansas City Royals as part of a three-team trade in which the Red Sox acquired Franchy Cordero, Josh Winckowski, and three players to be named later (identified in June as minor league prospects: outfielder Freddy Valdez from the Mets, and pitchers Grant Gambrell and Luis De La Rosa from the Royals)[43] while the New York Mets received Khalil Lee.

[46] He began the season batting .317 en route to being named the Royals' lone representative to the 2022 MLB All-Star Game.

[47] On July 27, 2022, the Royals traded Benintendi to the New York Yankees in exchange for minor league prospects T. J. Sikkema, Chandler Champlain, and Beck Way.

[51] Benintendi hit his first home run in a White Sox uniform on June 16 against the Seattle Mariners off of Bryan Woo.

Coupled with below average defense in left field, Benintendi registered a negative WAR (wins above replacement) for the first time in his career, excluding the 2020 COVID-shortened season.

[54] Benintendi's paternal grandparents immigrated to the United States from Castellammare del Golfo, Sicily, Italy, where they settled and lived on Lama Court in Gravesend, Brooklyn.