Gianni De Luca was born at Gagliato and moved to Rome to study architecture; however, he soon moved to comics and started his career as comics artists in 1946 for the magazine Il Vittorioso. In the late 1950s he started to collaborate with the Edizioni Paoline, a Catholic publisher, and with their weekly magazine Il Giornalino. In 1957–1959 he worked on La più grande storia mai raccontata ("The Greatest Story Ever Told"), a series of tales based on the Bible, and I dodici in cammino (a history of the Christian Church).
In 1969 he drew a western, Bob Jason, and started his most famous creation, Commissario Spada. For the series De Luca introduced a number of graphical innovations, which he later used also for the comics version of three Shakespeare's masterworks, Hamlet, The Tempest and Romeo and Juliet.
After the end of the Commissario Spada series in 1982, De Luca continued to work for Il Giornalino with an adaptation of Il giornalino di Gian Burrasca, the Adventure on the Orinoco, and comics biographies of Totò and Marilyn Monroe. These were followed by the science fiction series Paulus. In 1988 he worked on La freccia nera, followed by I giorni dell'impero, set in Imperial Rome and left unfinished after De Luca's death in Rome in 1991.