Large conductance Ca²⁺-activated K⁺ channels (BK_Ca) play a critical role in blood pressure regulation by tuning the vascular smooth muscle tone, and hyposensitivity of BK_Ca to Ca²⁺ sparks resulting from its altered 1 subunit stoichiometry underlies vasoconstriction in animal models of hypertension. Here we demonstrate hypersensitivity of BK_Ca to Ca²⁺ sparks that contributes to hypotension and blunted vasoreactivity in acute hemorrhagic shock. In arterial smooth muscle cells under voltage-clamp conditions (0 mV), the amplitude and duration, but not the frequency, of spontaneous transient outward currents of BK_Ca origin were markedly enhanced in hemorrhagic shock, resulting in a 265% greater hyperpolarizing current. Concomitantly, subsurface Ca²⁺ spark frequency was either unaltered (at 0 mV) or decreased in hyperpolarized resting cells. Examining the relationship between spark and spontaneous transient outward current amplitudes revealed a hypersensitive BK_Ca activity to Ca²⁺ spark in hemorrhagic shock, whereas the spark-spontaneous transient outward current coupling fidelity was near unity in both groups. Importantly, we found an acute upregulation of the 1 subunit of the channel, and single-channel recording substantiated BK_Ca hypersensitivity at micromolar Ca²⁺, which promotes the and 1 subunit interaction. Treatment of shock animals with the BK_Ca inhibitors iberiotoxin and charybdotoxin partially restored vascular membrane potential and vasoreactivity to norepinephrine and blood reinfusion. Thus, the results underscore a dynamic regulation of the BK_Ca-Ca²⁺ spark coupling and its therapeutic potential in hemorrhagic shock-associated vascular disorders.