Urquidy signed with the Houston Astros as an international free agent in 2015 under the name of José Luis Hernández, as he was known until the start of the 2019 season.

[9] Pitching in relief in Game 5, he earned the win with one scoreless inning, making him the winningest internationally born player in World Series history.

[10][11] On June 26, 2022, Urquidy started a contest with 6+1⁄3 hitless innings versus the New York Yankees before ceding a home run to Giancarlo Stanton.

Urquidy's performance extended a no-hit streak to 16+1⁄3 innings forged by Astros pitching, tying an expansion-era record.

[13] Urquidy spun seven scoreless innings on August 3 versus Boston, delivered a game score of 83 and tied his career high of 10 strikeouts on the way to a 6–1 win.

[14] On August 15, he hurled 7+2⁄3 hitless innings versus the Chicago White Sox until allowing his lone hit against A. J. Pollock before being removed.

[15] In a rematch of the prior year's World Series, Urquidy earned the win versus Atlanta after allowing two runs over seven innings, striking out six, as Houston won, 5–4.

[24] In the third-to-last regular season game of 2023, Urquidy made and won a spot start versus the Arizona Diamondbacks by authoring six shutout innings, which was instrumental in the Astros' postseason push in a tight AL West division race with Seattle and Texas.

[27] On November 4, 2024, Urquidy was removed from the 40–man roster to be sent outright to the Triple–A Sugar Land Space Cowboys, but he rejected the assignment and elected free agency.