Purpose: Neuroinflammation was indicated in the pathophysiology of Alzheimer’s disease. Previous reports have also signified that spironolactone has anti-inflammatory effects. Therefore, the aim of this study was to assess the modulatory effects of spironolactone on neuroinflammation and memory loss in a rat model of Alzheimer’s disease. Methods: The β-amyloid protein fragment 25-35 (Aβ) was injected in the dorsal hippocampus (5μg/2.5μl each side) of male Sprague-Dawley rats for four consecutive days to induce memory impairment. Animals have intraperitoneally received spironolactone (10, 25, or 50 mg/kg, N=6/group) or vehicle for 14 days. The passive inhibitory avoidance and the novel recognition tests were used for memory evaluation. Neuroinflammation was assessed by measuring the level of Iba1 protein, a marker of microglial activation, using western immunoblotting. Results: Different doses of spironolactone showed no significant changes in latency times and discriminations ratios in passive inhibitory avoidance and novel recognition tests, respectively, as compared to vehicle. However, spironolactone-treated groups showed significantly lower Iba1 protein levels in comparison to the vehicle-treated group (p<0.01). Conclusion: Spironolactone had a modulatory effect on neuroinflammation through a repressive effect on microglial activation with no valuable effect on memory improvement in a rat model of Alzheimer’s disease. The findings of this study suggest that Ab-induced memory loss may not be directly linked to microglial activation. Spironolactone may be a potential candidate to be examined in other neuroinflammatory disorders.