Background. Despite modern therapeutic armamentariums, malaria remains a 21st century public health menace. The issue of combating malaria is the ever-growing resistance to high-tech medications in which novel phytomedicines are highly demanding, a rapidly expanding research avenue. In Ethiopian folklore medicine, Urtica simensis has been used to treat malaria by drinking its juice after the dry roots have been mashed and combined with water. Hitherto, no in vivo study has been reported in the literature so far. To substantiate this folkloric claim, the present work herein was done. Methods. An acute oral toxicity study was conducted as per the standard protocol. To rule out, the extract’s inherent potential effects on bodyweight, basal body To, and PCV changes were tracked for two weeks. A four-day suppressive model and a curative assay model were utilized to investigate the antimalarial activity of the plant. Percent parasitemia suppression, packed cell volume, mean survival date, bodyweight, and rectal body temperature were used to determine antimalarial activity. Result. An acute toxicity study reveals that Urtica simensis was atoxic at a dose of 2000 mg/kg. It also affirms that U. simensis is free from intrinsic potential effects of interfering with bodyweight, temperature, and packed cell volume evolution. Both crude extract and its solvent fractions at all test doses exerted significant (
P
<
0.001
) inhibition of parasitemia as compared to the control group. CF400 mg/kg provided the greatest chemosuppressive effect (79.24%). In a curative experiment, crude extract and CF were able to prevent the cardinal indications of P. berghei-induced malaria, such as weight loss, hypothermia, parasitemia, and anemia. Both crude extracts and their solvent fractions prolong survival dates. Conclusion. The antimalarial activity of the crude extract and its solvent fractions was promising, confirming previous assertions. As a result, more research studies into chemical entities may be required.