Ginsenoside Rg1 (GS Rg1) is a glycosylated triterpenoid saponin extracted from Panax ginseng. We aim to investigate the impact of GS Rg1 on protein aggregation and inflammatory response in a cerebral ischemia/reperfusion (I/R) injury model. Rats were administered different doses of GS Rg1 (10, 20, or 40 mg/kg/day) or nimodipine (1 mg/kg/day) for 5 consecutive days. Cerebral I/R injury was induced by middle cerebral artery occlusion for 2 h followed by a 22 h reperfusion period. Next, we examined the differences in infarct volume and neurological deficit via TTC staining and Longa's scoring, respectively. Furthermore, the differences in protein aggregates, proteasome, IκBα and NF-κB in the cerebral cortices were investigated through western blotting. The distribution of ubiquitin, proteasome and NF-κB in the neocortex were examined through immunohistochemistry. Pro-inflammatory cytokines were measured using ELISA and proteasome activity was determined by fluorometric peptidaseassay. Treatment with GS Rg1 40 mg/kg resulted in a significantly lower infarct volume and improved the neurological deficit score as well as the histological appearance compared to the control I/R group (P < 0.05). GS Rg1 treatment resulted in significantly lower proinflammatory cytokine expressions and suppression of the nuclear translocation of NF-κB as well as the phosphorylation of IκBα (P < 0.01). Finally, GS Rg1 treatment decreased the proteasomal activity and protein aggregate accumulation in brain tissues (P < 0.01). Our results confirm the neuroprotective function of GS Rg1 at 40 mg/kg. This effect may be attributed to a decrease in ubiquitinated aggregates and a suppression of the inflammatory response after I/R insult.