Physiological functions of arterial smooth muscle cell ATP-sensitive K⁺ (K_ATP) channels, which are composed of inwardly rectifying K⁺ channel 6.1 and sulfonylurea receptor (SUR)-2 subunits, during metabolic inhibition are unresolved. In the present study, we used a genetic model to investigate the physiological functions of SUR2-containing K_ATP channels in mediating vasodilation to hypoxia, oxygen and glucose deprivation (OGD) or metabolic inhibition, and functional recovery following these insults. Data indicate that SUR2B is the only SUR isoform expressed in murine cerebral artery smooth muscle cells. Pressurized SUR2 wild-type (SUR2_wt) and SUR2 null (SUR2_nl) mouse cerebral arteries developed similar levels of myogenic tone and dilated similarly to hypoxia (<10 mmHg Po₂). In contrast, vasodilation induced by pinacidil, a K_ATP channel opener, was ∼71% smaller in SUR2_nl arteries. Human cerebral arteries also expressed SUR2B, developed myogenic tone, and dilated in response to hypoxia and pinacidil. OGD, oligomycin B (a mitochondrial ATP synthase blocker), and CCCP (a mitochondrial uncoupler) all induced vasodilations that were ∼39–61% smaller in SUR2_nl than in SUR2_wt arteries. The restoration of oxygen and glucose following OGD or removal of oligomycin B and CCCP resulted in partial recovery of tone in both SUR2_wt and SUR2_nl cerebral arteries. However, SUR_nl arteries regained ∼60–82% more tone than did SUR2_wt arteries. These data indicate that SUR2-containing K_ATP channels are functional molecular targets for OGD, but not hypoxic, vasodilation in cerebral arteries. In addition, OGD activation of SUR2-containing K_ATP channels may contribute to postischemic loss of myogenic tone.