The Messinian Salinity Crisis (MSC) was a marked late Neogene oceanographic event during which the Mediterranean Sea evaporated. Its causes remain unresolved, with tectonic restrictions to the Atlantic Ocean or glacio-eustatic restriction of flow during sea-level lowstands, or a mixture of the two mechanisms, being proposed. Here we present the first direct geological evidence of Antarctic ice-sheet (AIS) expansion at the MSC onset and use a δ(18)O record to model relative sea-level changes. Antarctic sedimentary successions indicate AIS expansion at 6 Ma coincident with major MSC desiccation; relative sea-level modelling indicates a prolonged ∼50 m lowstand at the Strait of Gibraltar, which resulted from AIS expansion and local evaporation of sea water in concert with evaporite precipitation that caused lithospheric deformation. Our results reconcile MSC events and demonstrate that desiccation and refilling were timed by the interplay between glacio-eustatic sea-level variations, glacial isostatic adjustment and mantle deformation in response to changing water and evaporite loads.