Vasoconstrictors that bind to phospholipase C–coupled receptors elevate inositol-1,4,5-trisphosphate (IP₃). IP₃ is generally considered to elevate intracellular Ca²⁺ concentration ([Ca²⁺]_i) in arterial myocytes and induce vasoconstriction via a single mechanism: by activating sarcoplasmic reticulum (SR)-localized IP₃ receptors, leading to intracellular Ca²⁺ release. We show that IP₃ also stimulates vasoconstriction via a SR Ca²⁺ release–independent mechanism. In isolated cerebral artery myocytes and arteries in which SR Ca²⁺ was depleted to abolish Ca²⁺ release (measured using D1ER, a fluorescence resonance energy transfer–based SR Ca²⁺ indicator), IP₃ activated 15 pS sarcolemmal cation channels, generated a whole-cell cation current (I_Cat) caused by Na⁺ influx, induced membrane depolarization, elevated [Ca²⁺]_i, and stimulated vasoconstriction. The IP₃-induced I_Cat and [Ca²⁺]_i elevation were attenuated by cation channel (Gd³⁺, 2-APB) and IP₃ receptor (xestospongin C, heparin, 2-APB) blockers. TRPC3 (canonical transient receptor potential 3) channel knockdown with short hairpin RNA and diltiazem and nimodipine, voltage-dependent Ca²⁺ channel blockers, reduced the SR Ca²⁺ release–independent, IP₃-induced [Ca²⁺]_i elevation and vasoconstriction. In pressurized arteries, SR Ca²⁺ depletion did not alter IP₃-induced constriction at 20 mm Hg but reduced IP₃-induced constriction by ≈39% at 60 mm Hg. [Ca²⁺]_i elevations and constrictions induced by endothelin-1, a phospholipase C–coupled receptor agonist, were both attenuated by TRPC3 knockdown and xestospongin C in SR Ca²⁺-depleted arteries. In summary, we describe a novel mechanism of IP₃-induced vasoconstriction that does not occur as a result of SR Ca²⁺ release but because of IP₃ receptor–dependent I_Cat activation that requires TRPC3 channels. The resulting membrane depolarization activates voltage-dependent Ca²⁺ channels, leading to a myocyte [Ca²⁺]_i elevation, and vasoconstriction.