The Florence Welch-fronted group will top the bill during one of the Spanish music festival's days between July 12-15, 2012.
The festival slot will be in support of their chart-topping album Ceremonials, which was released last month.
The Vaccines have also confirmed that they will be playing the music event, though they have not revealed what day they will appear.
Florence + the Machine are the second headline act to be announced for Benicassim after The Stone Roses were confirmed to play earlier this month.
Meanwhile, Florence + the Machine recently revealed plans to embark on a ten-date tour of the UK throughout March.
Watch the music video for Florence + the Machine's new single 'No Light, No Light' below: