Background: Ezrin exhibits aberrant expression across diverse cancer types and significantly contributes to cancer initiation and advancement. However, the precise mechanism by which Ezrin regulates M1/M2 macrophage polarization in prostate cancer (PCa) remains unclear. This study aimed to elucidate the role and mechanism of Ezrin in regulating M1/M2 macrophage polarization in PCa. Methods: Initially, Ezrin levels were evaluated in transfected cells using real-time quantitative PCR (RT-qPCR), followed by Western blotting (WB) to evaluate Ezrin expression levels in PCa PC-3 cells overexpressing Ezrin and treated with the Mitogen-Activated Protein Kinase (MAPK) and nuclear factor kappa B (NF-κB) pathway inhibitors PD0325901 and BAY11-7082. Colony formation and Transwell assays were used to assess cell proliferation, migration, and invasion abilities. Additionally, its effects on levels of epithelial-mesenchymal transition (EMT)-associated markers (E-cadherin, ZO-1, Vimentin, Snail Slug, β-Catenin) and pathway-associated proteins were examined. Subsequently, transfected PC-3 cells were co-cultured with macrophages, and the expression of Cluster of Differentiation 206 (CD206) and CD86 in macrophages was assessed using flow cytometry and RT-qPCR. The expressions of M1/M2 markers (tumor necrosis factor (TNF)-α, interleukin (IL)-6, inducible nitric oxide synthase (iNOS), IL-10, Arg1) in macrophages were also detected by RT-qPCR. Finally, the impact of PD0325901 and BAY11-7082 on macrophage polarization after Ezrin overexpression was investigated. Results: Ezrin expression decreased in the si-Ezrin group and increased in the oe-Ezrin group compared to the control group (p < 0.05). Overexpression of Ezrin heightened Ezrin expression, increased proliferative, migratory, and invasive potential of PC-3 cells, enhanced EMT transition ability, and upregulated pathway-related proteins compared to the control group (p < 0.05). However, expression of Ezrin decreased in the oe-Ezrin+PD0325901 group and oe-Ezrin+BAY11-7082 group compared to Ezrin overexpression alone, inhibiting the growth and migration capabilities of PC-3 cells, reducing the expression of EMT markers, and suppressing the activation of the MAPK/NF-κB pathway (p < 0.05). Compared to the control group, cells in the si-Ezrin group exhibited an increase in CD86, TNF-α, IL-6, and iNOS, meanwhile, those in the oe-Ezrin group displayed a rise in CD206, IL-10, and Arg1 (p < 0.05). Moreover, the addition of pathway inhibitors PD0325901 and BAY11-7082 resulted in reduced CD206, IL-10, and Arg1 expression, while enhancing CD86, TNF-α, IL-6, and iNOS expression compared to the oe-Ezrin group (p < 0.05). Conclusion: Ezrin facilitates the proliferation and metastasis of PCa cells by activating the MAPK/NF-κB pathway. Additionally, Ezrin induces M2 polarization of macrophages, exacerbating the progression of PCa.