[12] He made his MLB debut that day against the Miami Marlins, pitching a scoreless inning of relief, and was the 6th-youngest player in the NL.

In the game, he also notched his first two major league strikeouts, punching out Magneuris Sierra and Jazz Chisholm Jr. On April 28, Santos was optioned to the Giants' alternate site in Sacramento to make room for new outfielder Mike Tauchman.

[6] In 2022 playing in the minors for Sacramento and briefly for the ACL Giants Black, he was a combined 1-2 with one save and a 4.63 ERA in 35 games (2 starts) in which he pitched 35 innings.

On December 22, 2022, Santos was traded to the Chicago White Sox in exchange for minor league pitcher Kade McClure.

[17] On February 3, 2024, the White Sox traded Santos to the Seattle Mariners in exchange for right-handed pitcher Prelander Berroa and outfielder Zach DeLoach.