Seyrig grew up in Lebanon, Greece, France, and the United States and studied drama in Paris and at the Lee Strasberg Actors Studio in New York. Initially a stage actress, she was cast in director Alain Resnais's L'Année dernière à Marienbad (1961; Last Year at Marienbad) as a beautiful, idealized woman who resists a man's attempts at brainwashing. Her role in Resnais's Muriel (1963) won her a best actress award at the Venice Film Festival. Her more than 30 subsequent films included roles in François Truffaut's Baisers volés (1968; Stolen Kisses), as a garish beauty in the satire Mister Freedom (1968), as a lesbian vampire in Les Lèvres rouges (1971; Daughters of Darkness), and in Luis Buñuel's Le Charme discret de la bourgeoisie (1972; The Discreet Charm of the Bourgeoisie).

In later years Seyrig allied herself with the French feminist movement, and beginning in 1975—the year she portrayed a femme fatale in Marguerite Duras's India Song—she usually worked with women directors. Despite her many films she considered herself primarily a stage actress; she performed in both classic and contemporary plays, often with small experimental theatres in France.