Desalination could solve the grand challenge of water scarcity, but materials-based and conventional thermal desalination methods generally suffer from scaling, fouling and materials degradation. Here, we propose and assess thermodiffusive desalination (TDD), a method that operates entirely in the liquid phase and notably excludes evaporation, freezing, membranes, or ion-adsorbing materials. Thermodiffusion is the migration of species under a temperature gradient and can be driven by thermal energy ubiquitous in the environment. Experimentally, a 450 ppm concentration drop was achieved by thermodiffusive separation when passing a NaCl/H2O solution through a single channel. This was further increased through re-circulation as a proof of concept for TDD. We also demonstrate via molecular dynamics and experiments that TDD in multi-component seawater is more amenable than in binary NaCl/H2O solutions. Numerically, we show that a scalable cascaded channel structure can further amplify thermodiffusive separation, achieving a concentration drop of 25000 ppm with a recovery rate of 10%. The minimum electric power consumption in this setup can be as low as 3 Whe m−3, which is only 1% of the theoretical minimum energy for desalination. TDD has potential in areas with abundant thermal energy but limited electrical power resources and can contribute to alleviating global freshwater scarcity.