Born to Andalusian parents, who moved to North Africa to escape the fascism of Francisco "El Caudillo" Franco, he moved to France at the age of 12. His career started in French movies, where he appeared in many of Luc Besson's films, two of which brought huge success for him as well: The Big Blue (1988), and Léon (1994), known as the Professional in the United States. He has starred in such high-profile American movies as French Kiss (1995) with Meg Ryan and Kevin Kline, Mission: Impossible (1996) with Tom Cruise, Ronin (1998) with Robert De Niro, and Godzilla (1998), while not neglecting French productions either—e.g., The Visitors (1996) and The Crimson Rivers (2000). He had a prominent role in the 2006 revival of the Pink Panther franchise, playing the partner of Inspector Clouseau opposite Steve Martin. He will also be playing Captain Bezu Fache in the upcoming 2006 major motion picture, The Da Vinci Code.

He was married twice and has four children, two from each marriage. His first wife was Geneviève, with whom he has a daughter, Sandra (born in 1978), and a son, Mickael (born in 1980). His second wife is model Nathalie Dyszkiewicz, with whom he has a son, Tom (born 1996), and a daughter, Serena (born 1998). He maintains homes in Paris and in Los Angeles.

Reno was also involved in the production of the second sequel of the popular PlayStation 2 series Onimusha (Onimusha 3: Demon Siege), having his likeness created into the protagonist Jacques Blanc as well as providing the voice for the character.