Evidence shows that administration of D-galactose (D-gal) induces reactive oxygen species (ROS) production and inflammatory response resulting in neurodegenerative changes. Ursolic acid (UA), a triterpenoid compound, has been reported to possess antioxidant and anti-inflammatory properties. Our previous studies have demonstrated that UA could protect mouse brain against D-gal–induced oxidative damage. In the present study, we examined the protective effect of UA against D-gal–induced inflammatory response in the prefrontal cortex and explored the potential mechanism of its action. Our results showed that UA administration significantly improved behavioral performance of D-gal–treated mice in step-through test and Morris water maze task. One of the potential mechanisms of this action was decreased advanced glycation end products (AGEs), ROS, and protein carbonyl levels in the prefrontal cortex of D-gal–treated mice. Furthermore, the results also showed that UA significantly reduced the number of activated microglia cells and astrocytes, decreased the expression of CD11b and glial fibrillary acidic protein, downregulated the expression of iNOS and COX-2, and decreased interleukin (IL)-1β, IL-6, and tumor necrosis factor-α levels in the prefrontal cortex of D-gal–treated mice. Moreover, UA significantly decreased AGEs induced the expression of receptor for advanced glycation end products and inhibited NF-κB p65 nuclear translocation in the prefrontal cortex of D-gal–treated mice. The aforementioned effects of UA could attenuate brain inflammatory response.