The scourge of malaria epidemic is still felt in sub-Saharan Africa, especially in Nigeria, despite the dedicated efforts directed toward its eradication. Therefore, the search for new, affordable and more potent antimalarial drugs from plants, especially, has become frontline in recent times. Traditional plants like Phyllanthus amarus are said to possess numerous phytochemicals responsible for their notable biological activities. Objectives: This study evaluates the phytochemical constituents, acute oral toxicity and in vivo antiplasmodial activity of methanol extract and its solvent fractions using documented methods. Results: Results from our study highlight the nontoxicity of the methanol extract and fractions. Qualitative phytochemical analysis of the methanol extract indicated the presence of a wide array of phytochemicals, while quantitative analysis revealed alkaloids as the most abundant phytochemical in both the methanol extract (3.82±0.53%) and the chloroform fraction (2.96±0.48%). The chloroform fraction showed the greatest parasite suppression in early (87%) and established (96%) infections. However, the methanol extract showed greater prophylactic activity (93%) in comparison with the chloroform fraction (66%). Parasite suppression by the chloroform fraction in tissues showed a dose-dependent increase in suppression. Also, its amelioration on parasite-altered haematological indices was significant. Conclusion: The chloroform fraction of P. amarus methanol extract possesses antimalarial phytochemicals with a promising source of lead compounds for drug discovery. So, the compounds should be identified for study.