Del Rio made her first adult film in 1974, and is credited as the first non-white woman to achieve stardom in the adult industry. Her enduring popularity is based on her enthusiasm, genuine passion, talent for specific acts, oversized clitoris and sense of humor, as well as her lush exotic beauty. In a span of 13 years, she appeared in 81 pornographic films and countless “loops” – 10 minute film clips produced for use in sex shop peep shows. Footage from her films has been included in at least 20 compilations marketed as original films due to her tremendous popularity.

Though del Rio retired from adult films in 1984, in part due to the AIDS scare prevalent at the time, she returned to make six final films in 1986/87, following a stint as a bodybuilder, including the faux biopic Deep Inside Vanessa del Rio and The Devil in Miss Jones 3 for the notorious punk-inspired Dark Brothers. She then worked as a feature dancer and magazine model until tearing the meniscus in her knee onstage in 1996. After that she used her coding skills to create her own website, produce original content, continued to appear in magazines, and made special appearances at award shows and conventions. During and after her porn career she appeared on many TV shows as herself, including a 1996 episode of NYPD Blue. In 2008, she made a cameo opposite Bernie Mac in the film Soul Men.

In 2007, the German art book publisher TASCHEN released a deluxe, heavily illustrated biography, Vanessa del Rio: Fifty Years of Slightly Slutty Behavior edited by del Rio’s long time friend Dian Hanson.

A feature film, The Latin from Manhattan, based on del Rio’s life, written and directed by Thomas Mignone, and starring Vivian Lamolli as del Rio began production in 2019.