This study evaluated the therapeutic potential of masitinib, an oral tyrosine kinase inhibitor with activity against c-Kit and platelet-derived growth factor receptors (PDGFR), to reduce ischemic brain area and neurological deficit. Using a well-established filament model of ischemic stroke in rats, the responses to oral treatment with masitinib alone or in combination with recombinant tissue plasminogen activator (rt-PA) were compared to those after rt-PA (10 mg/kg intravenously (i.v.)) monotherapy. In both cases, two doses of masitinib were used—25 or 100 mg/kg, twice per day. Ischemic brain area and the neurological deficit were assessed using the triphenyltetrazolium chloride (TTC) method and behavioral neurological tests, respectively. Masitinib, as a single agent, reduced significantly the infarct size, as compared with the stroke control group. Brain ischemic area decreased from 9.14 to 4.36 % (25 mg/kg) or 2.60 % (100 mg/kg). Moreover, a combined treatment of masitinib with rt-PA produced a stronger effect than the one observed after each of the compound alone. The size of the brain ischemic area (rt-PA 1.67 %) was further reduced to 0.83 or 0.7 % at masitinib doses of 25 and 100 mg/kg, respectively. Masitinib reduced significantly brain ischemia induced by experimental stroke and potentiated the therapeutic effect of rt-PA.