The practice was selected ahead of five other architects, including DSDHA, to land the prestigious project to modernise key areas within the existing Grade II*-listed building.
HOK International, de Rijke Marsh Morgan, MUMA and Rick Mather Architects also missed out on becoming the first architects to work in the gallery since John Miller - who completed his Centenary Development in 2001.
Rick Mather withdrew before the completion of the selection exercise.
Caruso St John has been taken on initially for five years and will be asked to look at reworking the entrance to the building and the Clore Gallery.
According to a gallery spokesman, the firm stood out 'because it showed the best understanding of the challenges posed by the building.'
The spokesman added: 'The selection panel was impressed by Caruso St John's combination of a strong analytical approach with a sympathy for the art that is shown in the gallery.'