BACKGROUND Dragon fruit (Hylocereus polyrhizus) is one of the most common fruits in tropical countries, including Indonesia. The unique deep purple-colored pulp of the fruit is eaten whole and consumed as juice. However, the inedible thick peel is wasted, causing environmental issues. In this study, the toxic, cytotoxic, and antiplasmodium activity from various extract of H. polyrhizus peels were examined. MATERIAL AND METHODS We evaluated the cytotoxicity and antiplasmodial properties of the various peel extracts by using different organic solvents.The extraction of the peels was conducted using maceration to obtain pigment, n-hexane, dichloromethane, and ethyl acetate extracts. The toxicity of the extract was assessed using the brine shrimp lethality test, followed by WST assay to test in vitro cytotoxic properties and in vitro antiplasmodial properties in 2 Plasmodium falciparum strains (3D7 and W2). RESULTS The n-hexane, dichloromethane, and ethyl acetate extracts depicted various levels of activity, whereas the pigment extract did not show any activities. However, dichloromethane demonstrated a high toxicity level with LC₅₀ of 10.32±0.13 μg/mL and a weak cytotoxic level against SK-OV-3 cell lines (IC₅₀ of 560.86±0.63 μg/mL). Moreover, the dichloromethane and n-hexane extracts showed high and promising antiplasmodial activity with IC₅₀ 2.13±0.42 and 6.51±0.49 μg/mL, respectively. CONCLUSIONS The dichloromethane extract demonstrated high antiplasmodial activity. Our observations have elucidated the cytotoxic and antiplasmodial activity of the peel of dragon fruits and can be used as a foundation for further research into the isolation and bioactivity of secondary metabolites.