Rodriguez was born in San Antonio, Texas. Her mother, Carmen Milady Rodriguez (born Pared Espinal), is a native of the Dominican Republic, and her father, Rafael Rodriguez, was a Puerto Rican who served in the U.S. Army. She has a total of ten siblings and half-siblings. She was partly raised by her devoutly religious maternal grandmother and was brought up as one of Jehovah's Witnesses (her mother's religion), though she has since abandoned that faith.
Rodriguez moved to the Dominican Republic with her mother when she was eight and lived in Puerto Rico until the age of eleven, later settling in Jersey City, New Jersey. She dropped out of high school but later earned her GED; in total she was expelled from five schools. Rodriguez briefly attended business school before quitting to pursue a career in acting, with the ultimate goal of becoming a writer and director.
Having run across an ad for an open casting call and attending her first audition, Rodriguez beat 350 other applicants to win her first role in the low-budget 2000 independent film, Girlfight. With her performance as Diana Guzman, a troubled teen who decides to channel her aggression by training to become a boxer,
Rodriguez accumulated several awards and nominations for the role in independent circles, including major acting accolades from the National Board of Review, Deauville Film Festival, Independent Spirit Awards, Gotham Awards, Las Vegas Film Critics Sierra Awards, and many others. The film itself took home a top prize at the Sundance and won Award of the Youth at the Cannes Film Festival.
Subsequently, she has had notable roles in other successful movies, including The Fast and the Furious, Resident Evil, Blue Crush, and S.W.A.T.. In 2004, Rodriguez lent her voice to the video game Halo 2, playing a Marine. She also provided the voice of Liz Ricarro in the Cartoon Network series IGPX. From 2005 to 2006, she played tough cop Ana Lucia Cortez on the television series Lost during the show's second season (the character's first appearance was a flashback on season 1's finale, "Exodus: Part 1"), and returned for a cameo in the second episode of the show's fifth season "The Lie" in 2009 and again in the penultimate episode of the series What They Died For in 2010. In 2006, Rodriguez was featured in her own episode of G4's show Icons.
In 2008, she appeared in Battle in Seattle alongside Charlize Theron. Rodriguez next appeared in the fourth installment of the Fast & Furious franchise, which was titled simply Fast & Furious and released to theaters on April 3, 2009. Rodriguez starred in James Cameron's high-budget sci-fi adventure film Avatar, which was released to theaters on December 18, 2009. The film became the highest-grossing film in history and Rodriguez's most successful film to date.
She filmed Trópico de Sangre, an independent film based on the Dominican Republic's historic Mirabal sisters who were assassinated in 1960 by the Dominican dictator Trujillo for opposing his rule, the same year.
In 2010, Rodriguez appeared in Robert Rodriguez's Machete, which also co-starred Danny Trejo, Robert DeNiro and Steven Seagal. The film was opened to mostly positive reviews and earned $44 million in the box-office on a $10 million budget. In 2011, she appeared with Aaron Eckhart in the science fiction film Battle: Los Angeles which grossed over $200 million in the worldwide box office, becoming a blockbuster success. As of 20 July 2010, Rodriguez's films have grossed $1,272,734,719 in the United States and $3,686,521,043 worldwide.