The lipid scramblase TMEM16F catalyses the exposure of phosphatidylserine in platelets to initiate blood coagulation. TMEM16F is a member of the TMEM16 family comprising calcium-activated lipid scramblases and ion channels. We have combined cryo-EM with patch-clamp electrophysiology and liposomal assays to characterize the dual function of TMEM16F as a lipid scramblase and an ion channel. Cryo-EM analyses of the protein in the absence and presence of calcium reveal rearrangements induced by ligand binding. Functional characterization shows that both processes are activated by the same mechanism, but appear to be catalysed by distinct protein conformations.