We determined the contribution of vascular BK and L-type Ca²⁺ channel dysregulation to exaggerated mortality in cecal ligation/puncture (CLP)-induced septic BK channel β1-subunit knockout (BK β1-KO, smooth muscle specific) mice. CLP-induced hemodynamic changes and mortality were assessed over 7 days in wild-type (WT) and BK β1-KO mice that were either untreated, given volume resuscitation (saline) or saline + calcium channel blocker nicardipine. Some mice were sacrificed 24 hours post-CLP to measure tissue injury, vascular and immune responses. CLP-induced hypotension was similar in untreated WT and BK β1-KO mice, but BK β1-KO mice died sooner. At 24 hours post-CLP (mortality latency in BK β1-KO mice), untreated CLP-BK β1-KO mice showed more severe hypothermia, lower tissue perfusion, polymorphonuclear neutrophil infiltration-independent severe intestinal necrosis, and higher serum cytokine levels than CLP-WT mice. Saline resuscitation improved survival in CLP-WT, but not CLP-BK β1-KO mice. Saline + nicardipine treated CLP-BK β1-KO mice exhibited longer survival times, higher tissue perfusion, less intestinal injury and lower cytokines vs. untreated CLP-BK β1-KO mice. These improvements were absent in treated CLP-WT mice, although saline + nicardipine improved blood pressure similarly in both septic mice. At 24 hours post-CLP, BK and L-type Ca²⁺ channel functions in vitro were maintained in mesenteric arteries from WT mice. Mesenteric arteries from BK β1-KO mice had blunted BK/enhanced L-type Ca²⁺ channel function. We conclude that vascular BK channel deficiency exaggerates mortality in septic BK β1-KO mice by activating L-type Ca²⁺ channels leading to blood pressure-independent tissue ischemia.