Ischemic stroke is one of the major causes of human morbidity and mortality. The pathophysiology of ischemic stroke involves complex events, including oxidative stress and inflammation, that lead to neuronal loss and cognitive deficits. Palmatine (PAL) is a naturally occurring (Coptidis rhizome) isoquinoline alkaloid that belongs to the class of protoberberines and has a wide spectrum of pharmacological and biological effects. In the present study, we evaluated the impact of Palmatine on neuronal damage, memory deficits, and inflammatory response in mice submitted to permanent focal cerebral ischemia induced by middle cerebral artery (pMCAO) occlusion. The animals were treated with Palmatine (0.2, 2 and 20 mg/kg/day, orally) or vehicle (3% Tween + saline solution) 2 h after pMCAO once daily for 3 days. Cerebral ischemia was confirmed by evaluating the infarct area (TTC staining) and neurological deficit score 24 h after pMCAO. Treatment with palmatine (2 and 20 mg/kg) reduced infarct size and neurological deficits and prevented working and aversive memory deficits in ischemic mice. Palmatine, at a dose of 2 mg/kg, had a similar effect of reducing neuroinflammation 24 h after cerebral ischemia, decreasing TNF-, iNOS, COX-2, and NF- κB immunoreactivities and preventing the activation of microglia and astrocytes. Moreover, palmatine (2 mg/kg) reduced COX-2, iNOS, and IL-1β immunoreactivity 96 h after pMCAO. The neuroprotective properties of palmatine make it an excellent adjuvant treatment for strokes due to its inhibition of neuroinflammation. © 2023 Elsevier B.V.