Collapse of membrane lipid asymmetry is a hallmark of blood coagulation. TMEM16F of the TMEM16 family that includes TMEM16A/B Ca²⁺-activated Cl⁻ channels (CaCCs) is linked to Scott syndrome with deficient Ca²⁺-dependent lipid scrambling. We generated TMEM16F knockout mice that exhibit bleeding defects and protection in an arterial thrombosis model associated with platelet deficiency in Ca²⁺-dependent phosphatidylserine exposure and procoagulant activity and lack a Ca²⁺-activated cation current in the platelet precursor megakaryocytes. Heterologous expression of TMEM16F generates a small-conductance Ca²⁺-activated nonselective cation (SCAN) current with subpicosiemens single-channel conductance rather than a CaCC. TMEM16F-SCAN channels permeate both monovalent and divalent cations, including Ca²⁺, and exhibit synergistic gating by Ca²⁺ and voltage. We further pinpointed a residue in the putative pore region important for the cation versus anion selectivity of TMEM16F-SCAN and TMEM16A-CaCC channels. This study thus identifies a Ca²⁺-activated channel permeable to Ca²⁺ and critical for Ca²⁺-dependent scramblase activity during blood coagulation.