Del Toro's performance as despairing ex-con turned zealot Jack Jordan, in Alejandro González Iñárritu's 21 Grams (2003), earned him a second nomination for the Academy Award for Best Supporting Actor.

In 2018, he starred as Richard Matt in the Showtime miniseries Escape at Dannemora, for which he received a nomination for the Primetime Emmy Award for Outstanding Lead Actor in a Limited Series or Movie.

[12] Success in an elective drama course encouraged him to drop out of college and study with noted acting teachers Stella Adler and Arthur Mendoza, in Los Angeles, as well as at the Circle in the Square Theatre School in New York City.

[12] Del Toro continued to appear in film including The Indian Runner (1991), China Moon (1994), Christopher Columbus: The Discovery (1992), Money for Nothing (1993), Fearless (1993) and Swimming with Sharks (1994).

Del Toro also shared the screen with Robert De Niro in the big-budget thriller The Fan (1996), in which he played Juan Primo, a charismatic Puerto Rican baseball star.

A few months later, he stood out among a first-rate ensemble cast in Steven Soderbergh's Traffic, a complex dissection of the North American drug wars.

As Javier Rodriguez—a Mexican border policeman struggling to remain honest amid the corruption and deception of illegal drug trafficking—del Toro, who spoke most of his lines in Spanish, gave a performance that dominated the film.

Del Toro won the Academy Award for Best Supporting Actor, becoming the fourth living Oscar winner whose winning role was a character who speaks predominantly in a non-English language.

He then appeared in the film adaptation of Frank Miller's graphic novel Sin City, directed by Robert Rodriguez, and Things We Lost in the Fire, the English-language debut of celebrated Danish director Susanne Bier.

[15] Sean Penn, who won the 2009 Best Actor Oscar for his performance in Milk, remarked that he was surprised and disappointed that Che and del Toro were not also up for any Academy Award nominations.

"[16] For the final portions of the film (shown here), del Toro shed 35 pounds to show how ill Guevara had become near the end of his life in the jungles of Bolivia.

[19][20] Del Toro played The Collector in a mid-credits scene of Marvel Studios' superhero film Thor: The Dark World (2013) and later reprised his role in Guardians of the Galaxy (2014)[21] and Avengers: Infinity War (2018).

[32] In March 2012, he was granted an honorary degree by the Interamerican University of Puerto Rico for his influence on the cinema enterprise, during the celebration of the institution's centenary.

[34] Del Toro narrated the public service announcement entitled "Coral Reef", joining the Artists to the Rescue of the Environment campaign.