[5] He has said that his interest in public service developed at a young age from watching his parents' involvement in political campaigns and civic causes.

His father, Jessie Guzman, is a retired mathematics teacher from the Edgewood Independent School District on San Antonio's west side, and his mother, Marie "Rosie" Castro, is a community activist.

[6] He graduated with honors from Stanford University with a Bachelor of Arts in political science and communications and earned a Juris Doctor with his twin brother at Harvard Law School.

[11] In June 2011, Castro announced his candidacy for the newly drawn Texas's 35th congressional district's seat in the U.S. House of Representatives.

In 2017, San Antonio Express-News columnist Bruce Davidson questioned Castro's decision not to enter the 2018 U.S. Senate race against Republican incumbent Ted Cruz, a 2016 presidential candidate.

Davidson predicted that Castro could have defeated the announced candidate, Beto O'Rourke, representative of Texas's 16th congressional district based in El Paso, for the Democratic nomination.

Bonilla was defeated for House reelection after redistricting in 2006, and Dewhurst lost the 2012 Republican runoff Senate election to Cruz.

[25] In August 2019, Castro tweeted the names and employers of 44 San Antonio residents who had given the maximum allowable contribution to Trump's reelection campaign.

[27] In July 2020, following House Foreign Affairs Committee chairperson Eliot Engel's defeat for reelection, Castro declared his candidacy for chair.

The other candidates were the eventually victorious Gregory Meeks and Brad Sherman, who had defeated former chairperson Howard Berman in a 2012 primary.

[30] Castro votes with President Joe Biden's stated position 100% of the time, according to FiveThirtyEight analysis completed in January 2023.

[43] He sits on several boards of nonprofit organizations and institutions of higher education, including the National College Advising Corps.