Castillo grew up in Las Cruces, New Mexico, and played for Mayfield High School under coach Arturo Garibay. In 2002, as a sophomore, he was named NSCAA/Adidas High School State Player of the Year. He was one of the top players in New Mexico as he helped lead Mayfield High School to two state championships games.

He first gained the notice of professional teams in 2005 playing for his local club in the Dallas Cup, one of the world’s top youth tournaments. His team made it to the Dallas Cup final for the Super Group but lost to Atletico Paranaense of Brazil, 1–0.

In early August 2007, Mexico coach Hugo Sánchez called-up Castillo for the three upcoming friendlies with Colombia, Panama, and Brazil. On August 22, 2007 Castillo made his debut with the Mexico national team and entered at the 53rd minute in the friendly against Colombia. In March 2008 he was also a member of the Mexico U-23 squad which participated in the 2008 CONCACAF Men Pre-Olympic Tournament in order to qualify for 2008 Summer Olympics.

Castillo began his professional career with Santos Laguna of the Primera División de México. After becoming a first team regular at Santos, and winning the championship in 2008, Castillo transferred mid-season to Club América in January 2009. During the off-season, Castillo was on loan to Tigres UANL and played for them during the 2009/10 season. He scored his first goal for Tigres against his former side, Santos Laguna, on August 30, 2009.

He was called up by Sven-Göran Eriksson to be on the 23-man roster for the Mexico national team, but he was benched during the game against Honduras on August 20, 2008. On November 12, 2008, Castillo appeared in a friendly match against Ecuador in Phoenix, Arizona. He replaced Francisco Fonseca as Mexico beat Ecuador 2–1. He was called up for the national team again on January 28, 2009, in a friendly against Sweden. Castillo was called up to the national side for World Cup qualifiers against Costa Rica in Mexico City and Honduras in San Pedro Sula on March 28 and April 1, 2009 but was unable to travel to either match because he had “lost” his Mexico passport.

On June 29, 2009, he was asked about possibly playing for the United States, saying, “I would play for the United States. I’d want to talk to them first, but I want to play for the U.S. I think it would be a very good opportunity for me, for my career. If they call me I would play for them.” Castillo also said, “I have made my decision. I want to represent the country where I was born, the place where I live.”

On September 2009, Castillo was cleared by FIFA to join the United States national team. On October 31, 2009 Castillo reveals to Mexican media after a Tigres UANL match vs Estudiantes Tecos that he had received a call earlier that day and stated “I was called up for training with the U.S. team and I am expected to appear to play against Denmark ….I’m hoping to give a good impression”.

Castillo made his U.S. debut as a second-half sub in a friendly against Denmark in which they lost on November 18, 2009. He is now the second player to earn caps for both Mexico and the United States, joining Martin Vasquez, who played non-FIFA-recognized matches with Mexico in 1992 and 1993 before receiving official call-ups to the U.S. starting in 1996.

On November 23, 2011, Castillo agreed to being loaned to Club Tijuana; on June 7, 2012 he joined Tijuana, permanently.

Castillo has since been recalled to the USMNT under new head coach Jurgen Klinsmann, and started against Mexico on August 10, 2011.

On January 9, 2018, Castillo moved to the Colorado Rapids on a one year loan with an option to buy. Castillo made his debut on March 10, 2018 in a 1–2 loss to the New England Revolution. On June 1, 2018, he scored his debut goal for the club in a 1–2 loss to the Vancouver Whitecaps FC.

Ahead of the 2019 season, Castillo was traded to the New England Revolution in exchange for Kelyn Rowe. He made his debut on March 2, 2019 in a 1–1 draw with FC Dallas.

On January 17, 2020, Castillo made the move to Atlanta United after his option was declined by New England at the end of the 2019 season.