The voltage- and Ca²⁺-dependent gating mechanism of large-conductance Ca²⁺-activated K⁺ (BK) channels from cultured rat skeletal muscle was studied using single-channel analysis. Channel open probability (P_o) increased with depolarization, as determined by limiting slope measurements (11 mV per e-fold change in P_o; effective gating charge, q_eff, of 2.3 ± 0.6 e_o). Estimates of q_eff were little changed for intracellular Ca²⁺ (Ca²⁺_i) ranging from 0.0003 to 1,024 μM. Increasing Ca²⁺_i from 0.03 to 1,024 μM shifted the voltage for half maximal activation (V_1/2) 175 mV in the hyperpolarizing direction. V_1/2 was independent of Ca²⁺_i for Ca²⁺_i ≤ 0.03 μM, indicating that the channel can be activated in the absence of Ca²⁺_i. Open and closed dwell-time distributions for data obtained at different Ca²⁺_i and voltage, but at the same P_o, were different, indicating that the major action of voltage is not through concentrating Ca²⁺ at the binding sites. The voltage dependence of P_o arose from a decrease in the mean closing rate with depolarization (q_eff = −0.5 e_o) and an increase in the mean opening rate (q_eff = 1.8 e_o), consistent with voltage-dependent steps in both the activation and deactivation pathways. A 50-state two-tiered model with separate voltage- and Ca²⁺-dependent steps was consistent with the major features of the voltage and Ca²⁺ dependence of the single-channel kinetics over wide ranges of Ca²⁺_i (∼0 through 1,024 μM), voltage (+80 to −80 mV), and P_o (10⁻⁴ to 0.96). In the model, the voltage dependence of the gating arises mainly from voltage-dependent transitions between closed (C-C) and open (O-O) states, with less voltage dependence for transitions between open and closed states (C-O), and with no voltage dependence for Ca²⁺-binding and unbinding. The two-tiered model can serve as a working hypothesis for the Ca²⁺- and voltage-dependent gating of the BK channel.