Plasmepsin II (PL II), an aspartyl protease inhibitor of P. falciparum, plays a key role in the haemoglobin degradation inside the food vacuole. Besides, dihydrofolate reductase (DHFR), a small enzyme that plays a critical role in the building of DNA and other processes, is found to be involved in the reproduction of the parasites, P. falciparum and P. vivax. Recently more focus has been arrived in the treatment and cure of malaria through inhibition of these key enzymes, PL II protease and DHFR. The main aim of the present study is to find out the binding mode and hydrogen bond interactions of the lichen metabolites; depsides viz. atranorin (ATR) & lecanoric acid (LA), depsidone, salazinic acid (SA) and dibenzofuran, usnic acid (USA) derivatives with PL II protease and DHFR proteins through molecular docking simulations using glide module v5.5 (Schrodinger suite 2009) by flexible docking method. The docking results indicate that the dibenzofuran USA derivatives are showing impressive hydrogen bond and hydrophobic interactions with PL II protease, whereas the depsidone, SA shows satisfactory interactions and the depsides namely, ATR and LA with least interactions. With respect to the DHFR, depsides; ATR and LA are showing effective H-bond interactions with the DHFR protein active sites of the two species in different docking grids. Further, SA and USA derivatives are showing flat interactions with the active residues of the DHFR protein. From the above results, it is clearly evident that further studies can be attempted in designing similar such structure-based novel molecules with PL II and DHFR inhibitory activity.