Ischemic stroke results from the interruption of blood flow to the brain resulting in long-term motor and cognitive neurological deficits, and it is a leading cause of death and disability. Current interventions focus on the restoration of blood flow to limit neuronal death, but these treatments have a therapeutic window of only a few hours and do not address post-stroke cerebral inflammation. The complement system, a component of the innate immune system, is activated by natural immunoglobulin M (IgM) antibodies that recognize neoepitopes expressed in the brain after ischemic stroke. We took advantage of this recognition system to inhibit complement activation locally in the ischemic area in mice. A single chain antibody recognizing a post-ischemic neoepitope linked to a complement inhibitor (termed B4Crry) was administered systemically as a single dose after stroke and shown to specifically target the ischemic hemisphere and improve long-term motor and cognitive recovery. We show that complement opsonins guide microglial phagocytosis of stressed but salvageable neurons, and that by locally and transiently inhibiting complement deposition, B4Crry prevented phagocytosis of penumbral neurons and inhibited pathologic complement and microglial activation that otherwise persisted for several weeks after stroke. B4Crry was protective in adult, aged, male and female mice and had a therapeutic window of at least 24 hours after stroke. Furthermore, the epitope recognized by B4Crry in mice is overexpressed in the ischemic penumbra of acute stroke patients, but not in the contralateral tissue, highlighting the translational potential of this approach.