Benintendi attended Madeira High School in Madeira, Ohio. As a senior, he batted .564 with 12 home runs, 57 runs batted in (RBIs), and 38 stolen bases for the Mustangs baseball team, and was the ABCA/Rawlings National High School Player of the Year and Ohio Gatorade Baseball Player of the Year. He finished his high school career with an Ohio-record 199 career runs scored. Benintendi was drafted by the Cincinnati Reds in the 31st round of the 2013 Major League Baseball draft, but he did not sign with the team.
Benintendi enrolled at the University of Arkansas to play college baseball for the Arkansas Razorbacks baseball team. As a true freshman, he played in 61 games, with 60 starts and hit .276/.368/.333 with one home run and 27 RBI.
In 2015, Benintendi led the Southeastern Conference in batting average (.380), home runs (19), on-base percentage (.489), slugging percentage (.715), and walks (47). He was named the SEC Player of the Year. He also won the Baseball America College Player of the Year Award, the Dick Howser Trophy, and the Golden Spikes Award. Benintendi was considered one of the top prospects for the 2015 Major League Baseball draft.
Benintendi was drafted by the Boston Red Sox with the seventh overall selection in the 2015 Major League Baseball draft. He signed with the Red Sox, receiving a $3.6 million signing bonus. Benintendi made his professional debut with the Lowell Spinners of the Class A-Short Season New York–Penn League. He began the 2016 season with the Salem Red Sox of the Class A-Advanced Carolina League, and received a promotion to the Portland Sea Dogs of the Class AA Eastern League on May 15.
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. He made his major league debut on August 2 against the Seattle Mariners as a pinch hitter and recorded his first major league hit off of Hisashi Iwakuma on August 3. Benintendi recorded both his first major league triple and home run against the Detroit Tigers on August 21 in a 10-5 loss.
On October 6, in Game 1 of the 2016 American League Division Series against the Cleveland Indians, Benintendi hit a home run in his first postseason at-bat off Indians' pitcher Trevor Bauer. With the feat, Benintendi became the youngest Red Sox player to hit a home run in a postseason game. However, the Indians won the game by a score of 5-4 and the series 3-0. He ended the 2016 season with a .295 batting average, 31 hits, 14 RBI, two home runs, and one stolen base.
Benintendi started the 2017 season as part of the Red Sox' Opening Day Roster. He batted second as the Red Sox defeated the Pittsburgh Pirates by a score of 5-3. On July 4, against the Texas Rangers, Benintendi went 5-for-5 with 6 RBI, two home runs, and a double in the 11-4 victory.