Introduction: Strychnos lucida R. Br. or Songga was empirically used as an anti-malarial and immunostimulant in the Tetun tribe, Indonesia. However, almost all plants from the genus Strychnos contain the alkaloid toxic compound strychnine. Objectives: The aims of this study are to determine in vitro/in vivo anti-malarial activity, to analyze the selectivity index, and to measure the phytoconstituents of various extracts (water, ethanol, ethyl acetate, n-hexane) from S. lucida stem. Materials and Methods: In vitro anti-malarial study was conducted against Plasmodium falciparum 3D7-chloroquine-sensitive, and in vitro cytotoxic was performed against Monkey kidney Vero cell. Plasmodium berghei ANKA-chloroquine sensitive infected malaria mice were used as a model for evaluation of in vivo anti-plasmodial. Phytoconstituents profile was determined using Thermo scientific LC-HRMS, and the m/z data was analyzed using Compound Discoverer software with mzCloud MS/MS Library. Results: Water (W), Ethanol (E), and Ethyl Acetate (EA) extract exhibited more potential in vitro/in vivo anti-malarial activity than n-hexane (H) extract (IC 50 2.48±0.09; 2.45±0.02; 2.90±0.07; 7.64±0.30 μg/mL, respectively). The selectivity index of water, ethanol, ethyl acetate, and n-hexane extract are 211.47, 78.46, 249.62, and 32.39, respectively). According to the LC-HRMS profile, water and ethanol extract mainly contain alkaloid and phenolic compounds. Ethyl acetate and n-hexane mostly contain terpenoids and fatty acids. Conclusion: According to the result, we conclude that ethanol and water extract from S. lucida R. Br. display potential anti-malarial. Alkaloids and phenolic compounds probably have the most contribution to their anti-malarial activity.