Accordingly, the goals of this translational preclinical study were to determine whether (1) NHE‐1 inhibition before or after ischemic insult worsens neurovascular injury and functional outcomes in thromboembolic stroke, (2) activation of proton channel Hv1 contributes to detrimental effects of NHE‐1 inhibition after stroke, and (3) Hv1 contributes to neurovascular injury and poor outcomes in multiple models of stroke. The gene discussed is HVCN1; the disease is stroke disorder.