Lopez was born in New York City of Puerto Rican descent. Lopez began his acting career in theater, based in New York. He was signed to a contract at Warner Bros. Studios in 1954, his first appearance being Bogus Charlie in Drum Beat. Lopez appeared as Spanish Joe in Battle Cry (1955), as Rodrigues in Mister Roberts in 1955, then had the leading role in The Steel Jungle (1956) and appeared as Toro in Cry Tough in 1959. He also played in a number of B-movies and Westerns early on in his career, including the Creature from the Black Lagoon (1954), The Young Guns (1956) and The Lone Ranger.

Among his many television appearances, one of his more well-known roles is that of Esteban Rodriguez in the classic Star Trek episode "Shore Leave". Lopez also appeared in an episode of Bonanza, as the cold-blooded outlaw Duke Miller, who kills a man over being first in line to get a haircut. He was Joaquín Castañeda, a mestizo that fought to free his people, on Zorro, starring Guy Williams. Lopez also appeared in episode 14, "Night Of The Long Knives" originally airing December 16, 1966 of The Time Tunnel television series; the Voyage to the Bottom of the Sea episode "Savage Jungle"; McLintock! (1963) as Davey Elk; the Juan Moreno's Body as a migrant Mexican fruit picker accused of murdering the son of the owner of the orchard; and Kelly's Heroes (1970) as Pvt. Petuko.

Although he was part of the supporting cast in Mister Roberts, his role was prominent – he played opposite Henry Fonda and James Cagney, who were both established stars at the time. However, he was perhaps best known as Lieutenant Lou Escobar in the 1974 film Chinatown, which he starred in opposite Jack Nicholson and Faye Dunaway. He reprised the role sixteen years later (with Escobar promoted to Captain) in The Two Jakes in 1990. Also right before this time he starred opposite Charles Bronson playing drug gang leader Ed Zacharias in 1987's Death Wish 4: The Crackdown.