De Novo drug design aims at predicting the peptide leads for anti-malarial activity from the designed set of 200 templates (Dipeptide, tripeptide, tetrapeptide and pentapeptide 50 each). Lipinski rules of 5, Molinspiration and Swiss-dock strategy was applied to identify the most potent antimalarial lead against various enzyme targets. Initially, 43 compounds were selected from 200 templates through Lipinski filters and upon subjected to molinspiration further, only 5 leads (Arg-Ser, Asn-Ser, Pro-Lys-Ser, Pro-Lys-Gly and Pro-Lys-Thr) were identified and selected as good targets for enzyme dihydrofolate Reductase (DHFR), Dihydro Orotate Dehydrogenase (DHOD) and aspartic proteinase. Among the docking results obtained with all the three enzyme targets, we found that the dipeptide Arg-Ser is the most potent lead target against malarial enzyme DHFR, aspartic proteinase and DHOD with their corresponding full fitness energy -302413.88 kcal/mol, -287460.67 kcal/mol and -453848.82 kcal/mol respectively. Dipeptide Asn-Ser was identified as the second most lead against malarial enzyme DHFR, aspartic proteinase and DHOD with their full fitness energy -285057.65 kcal/mol, -264788.72 kcal/mol and -425186.51 kcal/mol respectively. The above findings clearly shows that dipeptide Arg-Ser and Asn-Ser are potent targets against malaria and can be explored further to test in vitro, in vivo potency to validate therapeutic efficacy through structured based drug design.