The Yankees first promoted Mesa to the major leagues on September 10, 2012.[6] Mesa made his major league debut on September 22, 2012, against the Oakland Athletics in the bottom of the 14th inning as a pinch runner with the score tied 9–9. Derek Jeter bunted him to second base, and one batter later, Alex Rodriguez hit a single up the middle which should have brought Mesa home, but Mesa stumbled as he rounded third base and missed the bag. This forced him to backtrack, preventing him from scoring the winning run in his first major league game.[7] He recorded his first major league hit, an RBI single, on October 1 against Boston Red SoxpitcherAndrew Bailey.
Mesa was named the International League Player of the Week for the week ending August 11, 2013.[8]
Mesa was released by the Yankees on September 1, 2013.[9]
On May 26, 2014, Mesa was traded to the Toronto Blue Jays along with P. J. Walters in exchange for cash considerations.[10] Mesa was assigned to the Double-A New Hampshire Fisher Cats on May 27, then sent to the Triple-A Buffalo Bisons on June 12. He re-signed with the Blue Jays in January 2015. On January 12, 2015 he was assigned to the Double-A New Hampshire Fisher Cats. On April 30, 2015 he was promoted to the Triple-A Buffalo Bisons. On May 30, 2015 he was demoted back to New Hampshire.[11] He elected free agency on November 7, 2015[12] and re-signed shortly afterwards.[13]
Mesa split the 2016 campaign between New Hampshire and Buffalo, accumulating a .241/.299/.372 batting line with five home runs, 22 RBI, and five stolen bases across 69 games. He elected free agency following the season on November 7, 2016.[14]
On February 16, 2018, Mesa signed with the York Revolution of the Atlantic League of Professional Baseball. He re-signed with team for the 2019 season, and became a free agent following the season. On February 11, 2020, Mesa signed with the Revolution for the 2020 season. Mesa did not play in a game in 2020 due to the cancellation of the Atlantic League season because of the COVID-19 pandemic. On March 23, 2021, Mesa re-signed with the Revolution for the 2021 season. He became a free agent following the season. On February 15, 2022, Mesa again re-signed with York for the 2022 season.[15] He became a free agent following the season.