Dihydrofolate reductase (DHFR) enzyme regulates de-novo folate synthesis in Plasmodium falciparum, hence a critical malaria drug target. Pyrimethamine inhibits DHFR, but resistance and lack of cross-species activity are key challenges. Therefore, this study is set to investigate more potent nitrogenous heterocyclic compounds against DHFR. Docking and MD simulations were employed to gain insight into the compounds’ binding free energies and conformational stabilities, while cross-species activity was determined using sequence alignment. Among the 500 screened compounds, PMD_01 (−12.2 kcal/mol), PMD_02 (−11.1 kcal/mol), PMD_03 (−10.7 kcal/mol), and PMD_04 (−10.7 kcal/mol) have the highest binding affinities against pfDHFR compared to pyrimethamine (−7.9 kcal/mol). Critical amino acids for binding interactions in the active site of pfDHFR include Leu45, Thr107, Ile164, and Thr170. PMD-bound systems showed higher binding free energy than pyrimethamine, except PMD_03. Hydrogen bonding interactions with Gly159, Ser101, Ser104, Ser160, Ile157, and Lys48 played significant roles in the binding interaction of these compounds as opposed to Asp53 in pyrimethamine. The four systems converged around 1.90 Å RMSD and showed more stability than pyrimethamine-bound and unbound pfDHFR. The pocket's residues across the four plasmodia were highly conserved, but Phe116 and Ile164 replaced Met in P. knowlesi and Tyr in the other species. PMD_01, PMD_02, PMD_03, and PMD_04 showed promising inhibition against pfDHFR and are, thus, potential antimalarial agents against plasmodia DHFR homologues.