The lineup was announced Tuesday and includes more than 300 features and shorts from 67 countries.
The Oct. 13 opener is "Never Let Me Go," an unsettling coming-of-age story starring Knightley, Carey Mulligan and Andrew Garfield. Clooney plays a world-weary assassin in "The American," while Portman is a dancer in ballet thriller "Black Swan."
Artistic director Sandra Hebron says the lineup of British films is one of the strongest in years. It includes the highly touted "The King's Speech," starring Colin Firth as the stuttering King George VI.
The festival runs Oct. 13 to 28.