The emergence of drug resistance parasite to currently available drugs and the spread of insecticide resistance mosquito vector is worrisome and may result in serious health crisis if it is not addressed. Hence, there is need to develop novel antiplasmodial agent that will be cheap and effective against the Plasmodium parasite. This study was aimed at investigating the acute toxicity and antiplasmodial activity of methanol extracts of Tetrorchidium didymostemon leaves and stem bark. Acute toxicity of the extracts was investigated using the Lorke’s method. Antiplasmodial activity in early infection was tested using the Peter’s 4-day suppressive test while Ryley and Peters’ curative test was used to investigate the effect of the extracts on established infection. No mortality was recorded in the acute toxicity study. The leaves extract at 250 and 500 mg/kg body weight had significantly higher (p < 0.05) chemosuppression (69.84% and 73.11%, respectively) of the Plasmodium berghei parasite when compared with the stem bark extract at similar concentrations (55.55% and 49.67 %, respectively). The leaves extract, at 500 mg/kg body weight, showed better curative potential (67.92%) with mean survival time (MST) of 20.4 days than the stem bark counterpart at 500 mg/kg body weight (48.37% and 18.6 days, respectively). This study has shown that methanol extract of T. didymostemon leaves contains bioactive compounds with antiplasmodial activity and it substantiates its therapeutic use locally in traditional medicine.