He made his professional debut in 2014 with the Dominican Summer League Dodgers and spent the whole season there, going 2–1 with a 1.05 ERA in twenty games.

[7] Santana was called up to the majors by the Dodgers for the first time on May 30, 2018[8] and made his debut on June 1, picking up the win in relief, despite allowing five runs on six hits in 32⁄3 innings against the Colorado Rockies.

[9] He was scheduled to make his first major league start on June 7 against the Pittsburgh Pirates but suffered a right rotator cuff strain while warming up in the bullpen before the game and was placed on the disabled list, where he remained for the rest of the season.

[12] On June 17, 2021, Santana was traded to the Texas Rangers in exchange for Kelvin Bautista and was assigned to the Triple-A Round Rock Express.

[20] After pitching a scoreless inning in a 3–2 loss against the Washington Nationals, Santana was designated for assignment the same day when Brooks Raley was activated from the injured list.

[24] On December 6, 2023, Santana signed a minor league contract with the New York Yankees that included an invitation to spring training.

[25] He began the season with the Triple-A Scranton/Wilkes-Barre RailRiders, and was promoted to the major leagues on April 5 when Jonathan Loáisiga was placed on the 60-day injured list.