Objective: To investigate in vitro antimalarial activity of chalcone derivative compounds against Plasmodium falciparum 3D7 (Pf3D7) strain and in silico antimalarial activity. Methods: Synthesis of the chalcone derivatives was conducted via Claisen-Schmidt method using NaOH 60％ base as catalyst. An in vitro antimalarial activity assay was carried out according to the Rieckmann method against the chloroquine-sensitive Pf3D7 strain. Molecular docking studies of the prepared compounds were performed using Discovery Studio 3.1 (Accelrys, Inc., San Diego, USA) software to dihydrofolate re-ductases–thymidylate synthase (PfDHFR-TS) protein with Protein Data Bank ID of 1J3I.pdb (sensitive-protein) and ID:4DP3.pdb (resistance-protein). Results: This work has successfully synthesized seven chalcone derivatives with a great antimalarial activity. It has been revealed that allyloxy, hydroxy and alkoxy functional groups could increase the antimalarial activity of the chalcone derivatives. The best antimalarial activity of the prepared compounds was possessed by 3b with an IC50 value of 0.59μM and categorized as an excellent antiplasmodial. Molecular docking studies of 3b showed binding interaction with the amino acid residues such as Ala16, Ile164, Phe58, Tyr170 of the 1J3I.pdb protein and also Ala16, Phe58, Ile112, Met55 of the 4DP3.pdb protein. Conclusions: An in vitro antimalarial assay of the prepared chalcone derivative (3a–g) showed an excellent and good antiplasmodial activity against the chloroquine-sensitive Pf3D7 strain. In silico antimalarial studies revealed that 3a–g made binding interaction with both sensitive-protein (1J3I.pdb) and resistance-protein (4DP3.pdb), which means that they were both active against chloroquine-sensitive and resistant plasmodium strain.