Macrophage polarization towards type 1 (M1) or type 2 (M2) is a critical determinant in re-establishing inflammation within the colon. Pomegranate is widely recognized as a biological source for its substantial quantity and potent anti-inflammatory properties. This investigation compares the effects of chitosan nanoparticles infused with pomegranate peel extract (Punica granatum L.) on the polarization of macrophages in mice's peritoneal fluid induced with dextran sodium sulfate (DSS). In this study, the male Balb/c mice were aged 12-16 weeks and had a body weight of 20-30 g. Randomly, six distinct groups of Balb/c mice were established. A total of 42 days of treatment, or 3 × 14 days, were administered in six treatment groups. After the experiment, the quantity of M1 and M2 macrophages in the peritoneal fluid was quantified through flow cytometric analysis. After administering 240 mg/kg chitosan-PPE nanoparticles (10.57±0.51%) increase in M2 macrophages was observed (p<0.05). Upon administration of 480 mg/kg chitosan-PPE nanoparticles (P2 groups) and unadulterated PPE at 480 mg/kg doses (P3 groups) and comparison to the DSS groups, a substantial increase in M2 macrophages (11.20±2.10%) and P3 groups (17.85±0.44%) was observed. In contrast, a concurrent decrease in M1 macrophages (67.23±2.18%) and P3 groups (60.33±8.42%) was observed (p<0.05). These results support the evidence notion that pomegranate peel extract has a significant anti-inflammatory effect and influences the polarization of macrophages. © 2025 the authors.