The Royal Fine Art Commission Trust and Sky judged the Lowry Centre in Salford Quays "a joy to see and fun to go into".
The building won the top prize on its architectural merits but also the part it has played in regenerating the area.
Other buildings picking up awards included the extension to the National Portrait Gallery in London and the Poetry Bus Shelter in Scotland's Edinburgh Park.
The special award for Young Architects went to The Royal Court Theatre in London and its architects, Haworth Tompkins.
The Lowry Centre, designed by architects Michael Wilford and Partners, was opened by former Culture Secretary Chris Smith last year and has since been visited by the Queen.
It houses the world's largest collection of paintings by LS Lowry, Salford's most famous son.
Fifty-five paintings and 278 drawings by Lowry, famous for his matchstick figures, are displayed on rotation.
The most expensive is Going to the Match, which was bought by the Football Association at auction for Â£1.9m.
At the Savoy Hotel award ceremony, Lord St John of Fawsley, chairman of the Trust, said: "It has been built in what was a declining area of Manchester, Salford Quays, and will play an important part in its revival.
"The building, unlike some in the south which may be better known, is user friendly, welcoming and bright.
"When we visited the centre it was thronged with young people not only eager to learn about Manchester's greatest artist but also to enlarge their knowledge and appreciation of modern art."
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