[1] He was selected by the Cincinnati Reds in the second round of the 2015 Major League Baseball draft.

He pitched 2016 with both the Billings Mustangs and Dayton Dragons, compiling a combined 3–3 record, 5.19 ERA, and 1.43 WHIP in 15 games started between both teams, and spent 2017 back with Dayton,[4][5] posting a 9–8 record and 3.38 ERA in 25 games (24 starts).

[11] Santillan made his MLB debut the next day as the starting pitcher against the Colorado Rockies, pitching 4+2⁄3 innings of 1-run ball with 5 strikeouts.

[13] He finished his debut campaign making 26 appearances and posting a 1–3 record and 2.91 ERA with 56 strikeouts in 43.1 innings pitched.

In 2022, Santillan pitched in 21 games for the Reds, registering a 5.49 ERA with 21 strikeouts in 19.2 innings of work.