[1] On December 20, 2014, Castillo and Kendry Flores were traded to the Miami Marlins for Casey McGehee.

[3] Castillo was part of a scuttled trade that briefly made him a member of the San Diego Padres organization in the summer of 2016.

On July 29, the Marlins traded Castillo along with Jarred Cosart, Josh Naylor, and Carter Capps to the Padres for pitchers Andrew Cashner, Colin Rea, and Tayron Guerrero.

[1] On January 19, 2017, the Marlins traded Castillo, Austin Brice, and Isaiah White to the Cincinnati Reds for starter Dan Straily.

[14] He started Game 2 of the Wild Card Series, picking up the loss against the Atlanta Braves after allowing one run in five innings in his postseason debut.

[18] He was the Reds' lone selection to the All-Star Game,[19] where he struck out two batters and allowed a single in an inning of work.

[20] On July 29, 2022, the Reds traded Castillo to the Seattle Mariners in exchange for prospects Noelvi Marte, Edwin Arroyo, Andrew Moore, and Levi Stoudt.

In Game 1 of the Wild Card Series, he threw 7+1⁄3 scoreless innings, striking out 5 and allowing 6 hits in a 4–0 Mariners win.

[25] He started Game 2 of the American League Division Series and continued his scoreless postseason streak until allowing a two-run home run to Yordan Alvarez in the sixth inning and picking up the loss against the Houston Astros.

[26][27] Castillo started on Opening Day in 2023, earning a win over the Cleveland Guardians after throwing six scoreless innings.

Castillo had an ERA of 2.84 after three months[28] and was named to his third All-Star Game, though he sat out the Midsummer Classic in Seattle.

[30][31] Castillo was the Mariners Opening Day starter again in 2024, this time losing to the Boston Red Sox.

[35] Early in his career, he combined a good changeup to go along with a fastball that averaged between 95 and 97 miles per hour and a slider.