De Santis apprenticed worked as camera operator for noted cinematographer Gianni Di Venzano on such classic films as Michelangelo Antonioni's "La Notte" (1961), Federico Fellini's "8 1/2" (1963) and Francesco Rosi's "The Moment of Truth" (1965). For the latter, De Santis succeeded his teacher when Di Vezano became ill and it marked the beginning of a long and fruitful collaboration between director and cameraman which included "Re: Lucky Luciano" (1973), "Bizet's Carmen" (1984) and "Chronicle of a Death Foretold" (1987).
Over his career, De Santis earned a reputation as a master of interior shots. In 1968, he earned a Best Cinematography Oscar for his lush, lyrical lensing of Franco Zeffirelli's "Romeo and Juliet". He was also responsible for the arresting images in Luchino Visconti's "The Damned" (1969) and, especially, "Death in Venice" (1971). De Santis went on to collaborate with directors as diverse as Robert Bresson ("Lancelot of the Lake" 1974; "L'Argent" 1983) and American Jerry Schatzberg ("Misunderstood" 1984).
While on location in the Ukraine shooting Rosi's "The Truce", De Santis suffered a fatal heart attack in June 1996.