Mazara began the 2016 season in Triple-A Round Rock. The Rangers promoted Mazara to the major leagues on April 10, following an injury to Shin-Soo Choo. In his MLB debut, Mazara batted second and hit a single off of Jered Weaver of the Los Angeles Angels of Anaheim in his first at bat to get his first major league hit. Mazara followed that up with another single, and in his third at bat, his first major league home run off of Weaver. Mazara provided the only run for the Rangers in his debut, going 3-for-4.[9][10] Mazara batted .333 in April, and won the American League Rookie of the Month Award.[11] On May 25, 2016, Mazara hit a massive 491-foot home run off of Angels starter Hector Santiago. Mazara continued to bat over .300 for the month of May and he yet again won the American League Rookie of the Month.[12]
To begin play in 2017, Mazara hit .417 with 2 home runs and 9 RBI's, one of those home runs being his first career Grand Slam which was hit on April 7 against the Oakland Athletics, propelling him to the American League Player of the Week. Mazara finished the 2017 season with a batting line of: .253/.323/.422/.745 with 20 home runs and a team leading 101 RBI.
In 2018, Mazara posted a batting line of .258/.317/.436/.753 with 20 home runs and 77 RBI. Mazara landed on the disabled list from July 20 to August 16 with a right thumb sprain. The injury lingered and hampered Mazara through the end of the season, but did not require surgery to fix.[13]
On June 21, 2019, Mazara hit a home run estimated at 505 feet off of Reynaldo López of the Chicago White Sox, the longest home run hit by any major leaguer in 2019.[14][15] In 2019, Mazara hit .268/.318/.469/.786 with 19 home runs and 66 RBIs.[16]
On December 11, 2019, Mazara was traded to the Chicago White Sox in exchange for Steele Walker.[16] Overall with the 2020 Chicago White Sox, Mazara batted .228 with one home run and 15 RBIs in 42 games.[17] On December 2, Mazara was non-tendered by the White Sox.[18]
On February 11, 2021, Mazara signed a one-year deal with the Detroit Tigers worth $1.75 million plus incentives.[19] On March 27, Tigers manager A. J. Hinch announced that Mazara had made the team's opening day roster.[20] Mazara played in 50 games for Detroit, slashing .212/.276/.321 with 3 home runs and 19 RBI. He was designated for assignment by the Tigers on July 16.[21] He was released by Detroit on July 23.[21]
On December 16, 2021, Mazara signed a minor league contract with the San Diego Padres.[22] He began the 2022 season with the El Paso Chihuahuas of the PCL. The Padres promoted Mazara to the major leagues on June 2.[23] The Padres designated Mazara for assignment on August 20.[24] He cleared waivers and elected free agency on August 23, 2022.
On December 6, 2022, Mazara signed a minor league contract with the Baltimore Orioles organization.[25] Mazara was released by the Orioles on March 27, 2023.[26]