Mayne, 61, is the first American in 14 years to win what is sometimes described as the architecture world's equivalent of the Nobel Prize.
He joins the likes of previous recipients American Frank Gehry, Britain's Sir Norman Foster, and Jorn Utzon, the Danish designer of the Sydney Opera House.
The Pritzker caps a three-decade career in which Mayne has designed buildings ranging from schools and office buildings to restaurants in places as far afield as South Korea, the Netherlands, Austria and California.
In Madrid, his firm Morphosis is creating a 10,000-sq metre public housing project and in Guadalajara, Mexico he is working on a 6,250-seat open-air arena due for completion in 2007.
The Pritzker jury citation said Mayne was a "product of the turbulent 60s who has carried that rebellious attitude and fervent desire for change into his practice."
Mayne said news of the award had left him speechless. "This is such a big deal ... it is not in my nature to think about being the one who prevails. For my whole life, I've always seen myself as an outsider."
Mayne was born in Connecticut and moved to Los Angeles when he was 10 years old.
"This is such a big deal ... it is not in my nature to think about being the one who prevails. For my whole life, I've always seen myself as an outsider"
He studied architecture at the University of Southern California and worked first as a planner before setting up his architecture firm Morphosis in Los Angeles in 1972.
His built works include the Sun Tower retail office building in Seoul, the ASE Design and Visitors Centre in Taipei, Taiwan and a movable stage set for the Charleroi Dance group in Belgium.
The Pritzker Prize, consisting of a bronze medallion and $100,000, was established in 1979 by the Pritzker family, who own the Hyatt hotel chain, as a means of honouring a living architect whose built works produce "consistent and significant contributions to humanity."
The last Americans to be awarded the prize were Robert Venturi in 1991, and Canadian-born Frank Gehry, designer of the Guggenheim Museum in Bilbao, Spain, in 1989.