Men with castration-resistant prostate cancer (CRPC) face poor prognosis and increased risk of treatment-incurred adverse effects resulting in one of the highest mortalities among patient population globally. Immune cells act as double-edged sword depending on the tumor microenvironment, which leads to increased infiltration of pro-tumor (M2) macrophages. Development of new immunomodulatory therapeutic agents capable of targeting the tumor microenvironment, and hence orchestrating the differentiation of pro-tumor M2 macrophages to anti-tumor M1, would substantially improve treatment outcomes of CRPC patients. We report, herein, Mangiferin functionalized gold nanoparticles (MGF-AuNPs) and its immunomodulatory characteristics in treating prostate cancer. We provide evidence of immunomodulatory intervention of MGF-AuNPs in prostate cancers through observations of enhanced levels of anti-tumor cytokines (IL-12 and TNF-α) with concomitant reductions in the levels of pro-tumor cytokines (IL-10 and IL-6). In the treated groups, IL-12 was elevated to ten-fold while TNF-α was elevated to about fifty-fold; while IL-10 and IL-6 were reduced by two-fold. Ability of MGF-AuNPs to target splenic macrophages is invoked via targeting of NF-kB signaling pathway. Finally, therapeutic efficacy of MGF-AuNPs, in treating prostate cancer in vivo in tumor bearing mice, is described taking into consideration various immunomodulatory interventions triggered by this green nanotechnology-based nanomedicine agent.