The rational design of eighteen new antimalarial compounds from xanthone derivatives has been conducted based on Quantitative Structure-Activity Relationship (QSAR) calculation using semiempirical AM1 methods. The best equation model obtained from QSAR calculation was Log pIC 50 = 2.997 -29.256 (qO8) -138.234 (qC9) -6.882 (qC12) -107.836 (qC14) + 48.764 (qO15). Among the designed compounds, 3,6-dihydroxy-9H-xanthen-9-one (26) and 3,4,6-trihydroxy-9H-xanthen-9-one (27) have been synthesized and investigated their in-vitro antimalarial activities against the chloroquine-sensitive 3D7 strain. An in-vitro antimalarial activity of compound 26 and 27 showed to be highly potential as antimalarial compounds with IC 50 of 0.71 and 0.11 µM respectively. Molecular docking studies of compound 26 and 27 showed the formation of a binding interaction between the compounds with the amino acids Ala16, Ser108, Phe58, Asp54 and Leu46, which is the crucial amino acids for antimalarial activity based on the protein-ligand co-crystal structure of WR99210 (1,3,5-triazine, a pre-clinical molecule as P. falciparum DHFR-TS inhibitor).