Cortical spreading depression is a pathophysiological event shared in migraines, strokes, traumatic brain injuries, and epilepsy. It is associated with complex hemodynamic responses, which, in turn, contribute to neurological problems. In this study, we investigated the role of canonical transient receptor potential channel 3 (TRPC3) in the hemodynamic responses elicited by cortical spreading depression. Cerebral blood flow was monitored using laser speckle contrast imaging, and cortical spreading depression was triggered using three well-established experimental approaches in mice. A comparison of TRPC3 knockout mice to controls revealed that the genetic ablation of TRPC3 expression significantly altered the hemodynamic responses elicited using cortical spreading depression and promoted hyperemia consistently. Our results indicate that TRPC3 contributes to hemodynamic responses associated with cortical spreading depression and could be a novel therapeutic target for a host of neurological disorders.