Objectives: In the present study, we targeted the dihydrofolate reductase enzyme that catalyzes the reduction of dihydrofolate to tetrahydrofolate which is required for the purines and pyrimidine synthesis. Malaria is one of the severe diseases throughout the world caused by blood-borne parasite Plasmodium vivax. Materials and Methods: Eighty-five parthenin analogs were docked against P. vivax and Homo sapiens dihydrofolate reductase proteins (PDB 2BL9 and 1KMS respectively) by using Maestro 9.6 program to evaluate the binding affinities of ligands with the protein. Results and Discussion:Docking analysis revealed some best hit ligands against P. vivax such as CID3467446 and CID56671343 but not inhibited the mammalian dihydrofolate reductase. The Dock score of parthenin analogs ranged from -7.31 to -9.3 while for standard dihydrofolate reductase inhibitors it was -4.78 to -8.04. Structural analysis of docked complexes of selected parthenin like compounds with P. vivax and mammalian dihydrofolate reductase revealed the involvement of Arg 115, Leu 136, Lys 138, Gly 175, Ser 117, Gln 177 and Ile 7, Ala 9, Thr 56, Ile 60, Pro 61 amino acid residues respectively in strong interactions. Absorption, distribution, metabolism, and excretion properties of best-docked compounds were predicted using QikProp application of Maestro 9.6. The results indicated that all the best-docked lead compounds followed Lipinski’s rule of five. Conclusion: Based on the results of the present study it has been concluded that parthenin like compounds may serve as potent dihydrofolate reductase inhibition based anti-malarial drug lead