As a rising fashion model, she was noticed by Jean-Luc Godard, then a film critic for Cahiers du cinéma. Her first film appearance, although unauthorized, dates from 1959, when a soap advertisement in which she appeared as a model was included near the end of Guy Debord's On the Passage of a Few Persons Through a Rather Brief Unity of Time. The image was accompanied by Debord's voice-over "The advertisements during intermissions are the truest reflection of an intermission from life." According to Godard's biographer, Colin Macabe, Godard was in the middle of casting his debut feature film, A bout de souffle, that same year when he saw Karina in a series of Palmolive ads in a bath covered in soapsuds. He offered her an important part in the film, which she turned down because of a nude scene. When Godard questioned her about her refusal, referring to the supposed nudity in the Palmolive ads, she is said to have replied "Are you mad? I was wearing a bathing suit in those ads — the soapsuds went up to my neck. It was in your mind that I was undressed." The character Godard had reserved for her did not appear in the film. However, she eventually accepted his offer to play a major role in Le Petit Soldat (1960). Godard and Karina married on 3 March 1961, during the shooting of Une femme est une femme, and divorced in 1967.
Karina was awarded best actress at the Berlin Film Festival in 1961 for her interpretation of the character Angela in the film Une femme est une femme. Her acting career was not, however, limited to Godard's films, and she went on to a successful collaboration with other well-known directors. Her role in Suzanne Simonin, la Religieuse de Diderot (1967) by Jacques Rivette is considered by some as her best performance. She also acted in Luchino Visconti's L'Etranger.
Other notable films include: George Cukor's Justine (1969), Tony Richardson's Laughter in the Dark (1969), Christian de Chalonge's L'Alliance (1970), Andre Delvaux's Rendezvous a Bray (1971), The Salzburg Connection (1972), Franco Brusati's Bread and Chocolate (1973) and Rainer Werner Fassbinder's Chinese Roulette (1976). In 1972 set up a production company named Raska for her film-directing debut Vivre Ensemble, in which she also acted and which was released in 1973. She wrote and acted in Last Song in 1987. She has since appeared in Haut, Bas, Fragile (1995) by Jacques Rivette and sung in The Truth About Charlie.
Karina has also maintained an important singing career. At the beginning of the 1960s, she scored a major hit with "Sous le soleil exactement" and "Roller Girl", both songs taken from the musical comedy Anna by Serge Gainsbourg in which she sings seven songs alongside Gainsbourg and Jean-Claude Brialy. She subsequently recorded an album entitled Une histoire d'amour with Philippe Katerine, which was followed up by a concert tour. Karina has also written three novels and made several appearances on television. In 2005 she released Chansons de films, a collection of songs sung in movies.