Introduction: In endemic malarial nations, repeated use of antimalarial drugs has increased due to resistance, misuse, and unrestricted availability, which could contribute to infertility rates. Therefore, we investigated the effects of long-term repeated treatment with two commonly prescribed artemisinin-based combination therapies, artemether/lumefantrine (A/L) and artesunate-amodiaquine (A/A), on reproductive potential in mice. Methods: Sixty male mice were divided into three groups: control, A/L, and A/A treatment. Mice underwent treatment for three consecutive days per week, and this regimen was repeated every two weeks for a total of six cycles. Sperm parameters were evaluated after the 1st, 2nd, 3rd, and 6th exposure cycles, after which treated male mice were paired with female mice for mating. Results: Sperm viability was significantly reduced by 21% (P<0.001) following the 6th exposure to A/L, whereas the 2nd, 3rd, and 6th exposures to A/A resulted in significant decreases in sperm viability of 26% (P<0.001), 12% (P<0.01), and 31% (P<0.001), respectively, compared to the control group. Treatment with A/A during the 3rd and 6th periods led to a significant decline (P<0.001) in sperm mass activity by 20% and 28%, respectively, compared to the control group. However, long-term therapeutic exposure to A/L or A/A did not affect testosterone levels, epididymal content, or the ability to impregnate female mice. Conclusion: Long-term treatment with A/L or A/A did not affect testosterone levels or epididymal content. However, a decrease in sperm viability was observed, even though the mice remained fertile.