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Methasterone (1) was subjected to biotransformation with Macrophomina phaseolina, Cunninghamella blakesleeana, and Fusarium lini.Eleven new (2–12) and one known (13) metabolites were obtained through this biotransformation.Compound 6 showed a potent inhibition against TNF-α and NO• in anti-inflammatory assay.All metabolites showed no cytotoxicity against 3T3 normal, and PC3, and HeLa cancer cell lines.Microbial transformation of methasterone (1) was investigated with Macrophomina phaseolina, Cunninghamella blakesleeana, and Fusarium lini. Biotransformation of 1 with M. phaseolina yielded metabolite 2, while metabolites 3–7 were obtained from the incubation of 1 with C. blakesleeana. Metabolites 8–13 were obtained through biotransformation with F. lini. All metabolites, except 13, were found to be new. Methasterone (1) and its metabolites 2–6, 9, 10, and 13 were then evaluated for their immunomodulatory effects against TNF-α, NO•, and ROS production. Among all tested compounds, metabolite 6 showed a potent inhibition of proinflammatory cytokine TNF-α (IC50 = 8.1 ± 0.9 μg/mL), as compared to pentoxifylline used as a standard (IC50 = 94.8 ± 2.1 μg/mL). All metabolites were also evaluated for the inhibition of NO• production at concentration of 25 μg/mL. Metabolites 6 (86.7 ± 2.3%) and 13 (62.5 ± 1.5%) were found to be the most potent inhibitors of NO• as compared to the standard NG-monomethyl-l-arginine acetate (65.6 ± 1.1%). All metabolites were found to be non-toxic against PC3, HeLa, and 3T3 cell lines. Observed inhibitory potential of metabolites 6 and 13 against pro-inflammatory cytokine TNF-α, as well as NO• production makes them interesting leads for further studies.