Over the past years, drug development direction has focused on the investigation of molecules that selectively target one protein. Executing rational combinations of targeted molecules will selectively regulate several pathways simultaneously. We aimed in this study to clear the relative therapeutic action between the outstanding agents silver nanoparticles (AgNPs), Spirulina (Sp), and a combination of them against bicalutamide (Casodex®) for the management of prostate cancer (PCa). PCa in rats was induced using bicalutamide and testosterone, followed by (7,12-dimethylbenz[a]anthracene). Rats were divided into six groups with 12 rats in each group. Group I was assigned as the control (co), group II as the PCa model, group III treated with AgNPs, group IV treated with Spirulina extract, group V treated with a combination of AgNPs plus Spirulina, and group VI treated with bicalutamide. Compared with bicalutamide treatment, AgNP treatment reduced the serum prostatic acid phosphatase (PAP) activity, improving PSA ratio, normalizing the IL-6 level, overcoming hormonal disturbance induced in PCa rats, and up-regulating P53, but it couldn't cure the pathological changes. Spirulina was significant up-regulated P53 and Caspase-3, in addition to regression of the histological pattern of high-grade prostatic intraepithelial neoplasia although the IL-6 level was still significantly high. Combination treatment decreased the PAP activity and up-regulating the expression of P53 and BAX, improving the pathological changes, increasing the E2 level and up-regulating the expression of BCL2 and TNF-α. Each of treatments has benefits and disadvantages over bicalutamide which need more experiments to discover the best combination, concentration, particle size and duration.