Malaria elimination worldwide is threatened to have a setback as artemisinin partial resistance emerge and spread in several regions. Development of novel antiplasmodial agent is crucial to overcome the resistance of antimalarial drugs, where it can be developed from natural resources with the knowledge of local people in endemic area. Here, we study the potential of Physalis angulata, which was the most potential among other medicinal plants used by the people in Papua Island. In vitro pfLDH assay was performed to evaluate antiplasmodial activity of medicinal plants screening and different extraction solvent comparison. Zebrafish embrio toxicity (ZET) was carried out to determine the toxicity profile of the extracts. In our findings, ethyl acetate extract of P. angulata was found to be the most active as antiplasmodial with IC₅₀ -value of 2.34 ± 0.64 µg/mL, followed by n-Hexane, water, and ethanol extract with IC₅₀ value of 19.94±2.58 µg/mL, 39.01±10.60 µg/mL, and >50 µg/mL, respectively. Toxicity study showed that water extract gave the highest LC₅₀ with the value of 754.41 µg/mL which considered as non-toxic, followed by ethyl acetate extract and n-Hexane extract with 15.38 and 14.20 µg/mL, respectively, which considered as moderately toxic. It is concluded that ethyl acetate extract of P. angulata showed promising potential as active antiplasmodial with moderately toxic profile and should be further studied to identifies the active and toxic substance contained to improve its activity and safety profile.