BACKGROUND The current study was designed to explore the pathway through which adipose-derived mesenchymal stem cells (ADMSCs) affect brain ischemic injury. MATERIAL AND METHODS The improving effect of ADMSCs on the brain function and structure was evaluated in a middle cerebral artery occlusion (MCAO) rat model. The permeability of the brain-blood barrier (BBB), inflammatory response, and endoplasmic reticulum (ER) stress-related signaling induced by ischemia were determined. RESULTS The administration of ADMSCs decreased neurological severity score when compared with that in the MCAO group and also restricted the brain infarction area as well as cell apoptosis. ADMSCs suppressed the inflammation in brains by decreasing the expressions of IL-1β, IL-6, and TNF-α, contributing to the decreased permeability of the BBB. The expressions of pro-apoptosis factors in ER stress were inhibited while that of anti-apoptosis factors were induced. CONCLUSIONS ADMSCs affected brain injury in multiple ways, not only by suppressing inflammation in the brain infarction area, but also by blocking ER stress-induced apoptosis.