Weisz, 34, won the award for playing the doomed Tessa Quayle, opposite British co-star Ralph Fiennes in a film directed by previously Oscar-nominated Brazilian filmmaker Fernando Meirelles.
Weisz (34) praised her "luminous acting partner" Fiennes, and novelist John LeCarre, who wrote the explosive story of immoral big-business on which the film was based.
She said his "unflinching, angry story really paid tribute to the people who are willing to risk their own lives to fight injustice.
"They are greater men and women than I," Weisz said.
Weisz studied at Cambridge University and worked as a model before breaking into film in Bernardo Bertolucci's coming-of-age movie 'Stealing Beauty' in 1996.
She beat out major competition for the award, including Michelle Williams for 'Brokeback Mountain', previous Oscar-winner Frances McDormand for the drama 'North Country', Amy Adams for 'Junebug' and Catherine Keener for her role as writer Harper Lee in 'Capote'.
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