Background: Malaria is prevalent in Nigeria, and artemether + lumefantrine (artemisinin-based combination therapy [ACT]) is drug of choice in treatment of uncomplicated cases. ACT is contraindicated in early pregnancy. They release-free radicals that can compromise female fertility. Infertility and its associated complications such as miscarriages, abnormal gestation, and unstable marriages seem to be on the increase. This study aims at evaluating the effect of ACT on female fertility. The significance of this research is to draw the attention of fertility care givers to this possible cause of infertility and fertility challenges. Subjects and Methods: Creighton Model FertilityCare System and NaProTECHNOLOGY are simply technologies that can be used to assess female fertility. They are used in this study to assess the effect of ACT administered at different stages of menstrual cycles of three selected fertile adult females. The results are interpreted on the background of standard Creighton model chart. Results: This study has shown that ACT has a significant fertility deteriorating effect on the women. It caused ovulation defect and diagnosed as partial rupture syndrome in the very cycle of use and in the first cycle after use. It also significantly reduced cervical mucus production and significantly reduced luteal phase progesterone production with an associated significant increase of luteal phase estrogen production. Conclusion: ACT use as antimalarial may be a possible cause of infertility and fertility challenges in women.