Background and objective: Chuquiraga spinosa Lessing (ChS) has shown protective effect on N-Nitroso-N-methylurea (NMU)-induced prostate cancer in rats. Currently, statins are being studied for their pro-apoptotic and antimetastatic effects. The main objective of this research was to determine the protective effect associated with the oral administration of simvastatin and ethanolic extract of the aerial parts of ChS in the prevention of prostate cancer. Methods: Fifty-six albino male rats were randomized into seven groups: I) negative control: physiological serum: 2 mL/kg; II) TCN: testosterone 100 mg/kg + cyproterone 50 mg/kg + NMU 50 mg/kg; III) TCN + S40 (simvastatin 40 mg/kg); IV) TCN + ChS250 (ChS 250 mg/kg); V) TCN + ChS50 (ChS 50 mg/kg) + S40; VI) TCN + ChS250 (ChS 250 mg/kg) + S40; and VII) TCN + ChS500 (ChS 500 mg/kg) + S40. The antioxidant activity was tested by using (2,2-diphenyl-1-picrylhydrazyl) (DPPH) assay. Hematology, toxicological biochemical parameters, prostate-specific antigen (PSA), histology and prostate size were evaluated as main indicators of protective effect. Results: Triglyceride values were decreased in the groups receiving ChS, being significant (P=0.02) in IV and VII group compared to cancer-inducing group (TCN). In groups that received ChS, PSA levels (P=0.71) were significant compared with TCN group. The VII group had the lowest prostate volume by sonography. The TCN group showed multiple foci of high-grade prostatic intraepithelial neoplasia (HG-PIN) with the presence of cells in mitosis; whilst, groups V and VI had few areas of HG-PIN. Conclusion: In experimental conditions, the ethanolic extract of C. spinosa in association with simvastatin showed a protective effect on prostate cancer through hypolipidemic and antioxidant activity.