Lovastatin, a pleiotropic cholesterol-lowering statin, possesses anti-inflammatory and immunomodulatory properties, yet its role in inflammatory bowel disease (IBD) remains unclear. This study investigates the anti-inflammatory effects of lovastatin in a dextran sulfate sodium (DSS)-induced colitis mouse model. We hypothesized that lovastatin alleviates colitis by modulating macrophage polarization via the PPARγ-NF-κB pathway. In vivo, lovastatin treatment mitigated the pathological features associated with colitis, such as body weight loss, disease activity index, colon length shortening, and colonic damage, and restoring the integrity of the intestinal mucosal barrier by preserving goblet cells and increasing tight junction proteins. Furthermore, lovastatin induced a shift in the macrophage phenotype from pro-inflammatory M1 macrophages to anti-inflammatory M2 macrophages, and downregulated M1-associated cytokines while upregulating M2 markers. RNA-seq revealed that PPARγ and NF-κB pathway may be involve in the regulation of macrophage polarization by lovastatin. In vitro, lovastatin dose-dependently inhibited LPS-induced M1 polarization in RAW264.7 cells and promoted M2 polarization via PPARγ activation, which suppressed NF-κB nuclear translocation. Mechanistically, PPARγ inhibition (GW9662) abolished lovastatin's effects, confirming PPARγ-NF-κB crosstalk. These findings demonstrate that lovastatin ameliorates colitis by rebalancing macrophage polarization through PPARγ-mediated NF-κB suppression, supporting its repurposing as a potential IBD therapy.