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Introduction: testicular histomorphology and hormonal alterations have been reported in few artemisinin-based combination therapies (ACTs) used for treatment of malaria. We are first to comparatively characterize possible gonadotoxicities from seven commercially available ACTs in an experimental model. Forty adult male Wistar rats were allotted (n = 8) groups of animals (n = 5) each. Group 1, normal control (NC) received placebo, while Groups 2 to 8 received oral therapeutic combined doses of artesunate-amodiaquine (AA) 5.71 mg, artesunate-mefloquine (AM) 19.29 mg, artesunate-sulfadoxine-pyrimethamine (ASP) 10.35 mg, artesunate-pyronaridine (APy) 10.29 mg, artemisinin-piperaquine (AP) 12.5 mg, dihydroartemisinin-piperaquine (DP) 15.42 mg, and artemether-lumefantrine (AL) 8 mg respectively for three days, except AP administered for two days (standard regimen). Animals were euthanized 24 hours after last administration under ketamine-xylazine anesthesia. Serum and testes were analyzed for hormonal and histomorphological alterations. Testosterone demonstrated increasing concentration with significant (p < 0.05) increase in AA, APy and AP-administered groups with corresponding decrease in prostate specific antigen. Sperm counts and motility significantly (p < 0.05) decreased in ACT-administered groups. Antioxidants catalase and superoxidedismutase levels in ASP, APy and DP-administered groups significantly decreased in correlation with elevated oxidative stress markers in ASP, APy and DP-administered groups. Widening of germinal epithelium, basement membrane distortion and spermatogonial cells degeneration were prominently demonstrated in ASP, APy, AP and DP-administered groups. In conclusion, oral therapeutic exposures to ACTs elicited gonadotoxicity with testiculo-microstructural, hormonal and antioxidant alterations ranging from mild to severe; AA, AP, AL, AM, APy, DP to ASP, respectively and generally decreasing PSA level. [ABSTRACT FROM AUTHOR]