Effects of silibinin, a naturally occurring flavanone, on prostate carcinoma (PCa) cells in presence of arsenic are not known. Arsenic is clinically approved for leukemia treatment; however, studies are not enough to support its role in the management of solid tumors. In the present study, we observed that silibinin (100 µM) modulated the oxidative status of human PCa DU145 cells exposed to arsenic (0.5 or 5 µM) and inhibited cell growth and survival by primarily inducing autophagy and apoptosis. The silibinin-arsenic combination also inhibited the growth, survival, and clonogenic potential of 22Rv1 PCa cells. Silibinin with 0.5 or 5 µM arsenic induced G1 or G2/M phase arrest, respectively, and decreased the protein levels of CDK2, -4, and -6 and cyclin D1, D3, and E and increased CDK inhibitors p21 and p27. Arsenic alone increased cyclin B1 level and Cdc2 kinase activity which were reduced in silibinin combination. Cell motility and invasiveness along with expression of MMP-2 and vimentin were suppressed. Together, these in vitro findings suggest that in presence of arsenic, silibinin strongly inhibits tumorigenic and metastatic potential of PCa cells.