In 1936, Rey began his career in movies as an extra, sometimes even getting credited. It was then that he chose his stage name, Fernando Rey. He kept his first name, but took his mother's second surname, Rey, a short surname with a clear meaning ("Rey" is Spanish for "King").

In 1944, his first speaking role was the Duke of Alba in José López Rubio's Eugenia de Montijo. Four years later, he acted the part of Felipe I el Hermoso, King of Spain, in the Spanish cinema blockbuster Locura de amor.

This was the start of a prolific career in film (he played in around two hundred films), radio, theatre, and television. Rey was also a great dubbing actor in Spanish television. His voice was considered intense and personal, and he became the narrator of important Spanish movies including Luis García Berlanga's Bienvenido Mr. Marshall (1953), Ladislao Vajda's Marcelino Pan y Vino (1955), and even the 1992 re-dubbed version of Orson Welles' Don Quixote. In fact, Rey acted in four different film versions of Don Quixote in different roles, if one counts the Welles version (for which Rey supplied offscreen narration in the final scene).

His brilliant performance in the role of a demotivated and doubtful actor in Juan Antonio Bardem's Cómicos (1954), while showing him for the first time in a successful lead part, paradoxically, as he saw himself as the real incarnation of the role, plunged him in a professional depression, of which he did not emerge until his collaboration with Luis Buñuel several years later. However, in the short term, Buñuel's disconcerting public remark on Rey's performance in another of Bardem's film, Sonatas (1959), "I love how this actor plays a corpse", could only increase Rey's apprehensions. Nevertheless, eventually Rey became Buñuel's preferred actor and closest friend.

Rey's first international performance was in The Night Heaven Fell (Les bijoutiers du clair de lune) a 1958 French-Italian film directed by Roger Vadim, where he acted alongside Stephen Boyd, Marina Vlady and Brigitte Bardot. Previously he had played in an American TV series, It happens in Spain, the story of the exploits of a private detective, operating out in Spain, who helps distressed American tourists.

In 1959, Rey co-starred with Steve Reeves and Christine Kaufmann in the Italian sword and sandal film The Last Days of Pompeii.

In 1960, Rey married the Argentine Actress Mabel Karr. In 1992 he became chairman of the Spanish Movie Arts and Sciences Academy. He died of bladder cancer in Madrid in 1994.

In 1961 Rey played in a European Western, The Savage Guns, and as the popularity of that genre increased during that decade appeared in some other movies, including the political The Price of Power (1969), the bizarre cult classic Compañeros, and two sequels of The Magnificent Seven, namely Return of the Seven (1966) and Guns of the Magnificent Seven (1969).

Along 1970s and 1980s Rey played in many international co-productions, some of his appearances being cameos. These films include Lewis Gilbert's The Adventurers (1970), Mauro Bolognini's Drama of the Rich (1974), Vincente Minnelli's A Matter of Time (1976), Valerio Zurlini's The Desert of the Tartars (1976), Robert Altman's Quintet (1979), J. Lee Thompson's Caboblanco (1980) and Frank Perry's Monsignor (1982). One of Rey's greater successes in these years was Elisa, vida mía, a 1977 Spanish drama film written and directed by Carlos Saura.

In 1971 Fernando Rey won the best actor award in the San Sebastián International Film Festival, for his performance in Rafael Gil's La duda, based, like Viridiana and Tristana, on a novel by Benito Pérez Galdós.

In Lina Wertmüller's Academy Award-nominated film, Seven Beauties (1975), Rey played the role of Pedro the anarchist who, as a friend of the protagonist and fellow prisoner Pasqualino Settebellezze, chooses a gruesome suicide, rather than spend another day in a Nazi concentration camp.

On his work in Stuart Rosenberg's Voyage of the Damned (1976), Rey once said: "I played [Cuban] President Brú; a cameo. They paid me a lot of money for less than six hours of shooting, in the Barcelona Stock Exchange building, with James Mason. I got more money than Orson Welles, who played a great role ...".

Rey won Best Actor award at 1977 Cannes Film Festival for his performance in Elisa, vida mía.

In later years, Rey preferred to work in Spain, with successes as Francisco Regueiro's Padre Nuestro (1985), José Luis Cuerda's El bosque animado (1987) and Jaime de Armiñán's Al otro lado del túnel (1992) as well as his portrayal of Don Quixote, alongside Alfredo Landa as Sancho Panza, in the memorable Manuel Gutiérrez Aragón's El Quijote de Miguel de Cervantes (1991) for the Spanish National TV.

In 1988 he again won the best actor award in the San Sebastián International Film Festival, this time for his performance in two films: Francisco Regueiro's Diario de invierno and Antonio Isasi-Isasmendi's El Aire de un Crimen (The Hint of a Crime).

His last appearance on the screen was in a supporting role in the Spanish black comedy El cianuro ... ¿sólo o con leche? (Cyanide ... pure or with milk?) (1994).