Elevations in cerebral metabolism necessitate appropriate coordinated and localized increases in cerebral blood flow (i.e. neurovascular coupling; NVC). Recent pre-clinical work indicates that arterial P_CO2 (P_aCO2) mediates NVC independently of arterial/extracellular pH; this has yet to be experimentally tested in humans. The goal of this study was to investigate the hypotheses that: (1) the NVC response would be unaffected by acute experimentally elevated arterial pH; rather, P_aCO2 would regulate any changes in NVC; and (2) stepwise respiratory alkalosis and acidosis would each progressively reduce the NVC response. Ten healthy males completed a standardized visual stimulus-evoked NVC test during matched stepwise iso-oxic alterations in P_aCO2 (hypocapnia: −5, −10 mmHg; hypercapnia: +5, +10 mmHg) prior to and following intravenous NaHCO₃ (8.4%, 50 mEq/50 ml) that elevated arterial pH (7.406 ± 0.019 vs. 7.457 ± 0.029; P < 0.001) and [HCO₃^–] (26.2 ± 1.5 vs. 29.3 ± 0.9 mEq/l; P < 0.001). Although the NVC response was collectively attenuated by 27–38% with −10 mmHg P_aCO2 (stage post hoc: all P < 0.05), this response was unaltered following NaHCO₃ (all P > 0.05) irrespective of the higher pH (P = 0.002) at each matched stage of P_aCO2 (P = 0.417). The absolute peak change was reduced by −19 ± 41% with +10 mmHg P_aCO2 irrespective of acutely elevated arterial pH/[HCO₃^–] (stage post hoc: P = 0.022). The NVC kinetics (i.e. time to peak) were markedly slower with hypercapnia versus hypocapnia (24 ± 5 vs. 7 ± 5 s, respectively; stage effect: P < 0.001). Overall, these findings indicate that temporal patterns in NVC are acutely regulated by P_aCO2 rather than arterial pH per se in the setting of acute metabolic alkalosis in humans.