Cosmatos found success in Italy for directing the films Rappresaglia (1973) with Marcello Mastroianni and The Cassandra Crossing (1976) with Sophia Loren.

In 1979, he made the British World War II adventure film Escape to Athena, starring an all-star ensemble cast including Roger Moore, David Niven, Telly Savalas, Elliott Gould and Claudia Cardinale.

[4] In 1989, he directed the science-fiction horror film Leviathan, starring Peter Weller, Richard Crenna, Ernie Hudson and Amanda Pays, with special effects designed by Stan Winston.

Late in his career, Cosmatos received more praise for Tombstone, a 1993 Western movie about Doc Holliday and Wyatt Earp.

Outside of his film career, Cosmatos was a collector of rare books, focusing mainly on 19th–20th Century English literature and signed & inscribed works.