There is an increasing need for innovative drug and prophylaxis discovery against malaria. The aim of the present study was to test in vivo antiplasmodial activity of Croton macrostachyus H. (Euphorbiaceae) stem bark extracts from Kenyan folkloric medicine. Inbred Balb/c mice were inoculated with erythrocytes parasitized with Plasmodium berghei (ANKA). Different doses (500, 250, and 100 mg/kg) of C. macrostachyus ethyl acetate, methanol, aqueous, and isobutanol extracts were administrated either after inoculation (Peters’ 4-day suppressive test) or before inoculation (chemoprotective test) of the parasitized erythrocytes. All the extracts showed significant suppression of parasitemia compared to control (𝑝 < 0.001): for the ethyl acetate extract in the range of 58–82%, for the methanol extract in the range of 27–68%, for the aqueous extract in the range of 24–72%, and for the isobutanol extract in the range of 61–80%. Chemoprotective effect was significant (𝑝 < 0.001) and the suppression caused by the ethyl acetate extract was between 74 and 100%, by the methanol extract between 57 and 83%, and by the isobutanol extract between 86–92%. The study showed that it is possible to inhibit the growth of the parasites by various stem bark extracts of C. macrostachyus in Balb/c mice supporting the folkloric use of the plant against malaria.