The Plasmodium falciparum dihydrofolate reductase (PfDHFR) and dihydroorotate dehydrogenase (PfDHODH) are essential for Plasmodium falciparum growth and development, and have been validated as targets for the development of new antimalarial agents. Several alkaloids isolated from Cryptolepis sanguinolenta have been reported to have antiplasmodial activity, but their protein targets are unknown. Therefore, molecular docking and molecular dynamics simulations were used to investigate the interactions and stability of the alkaloids with PfDHFR and PfDHODH. Based on physicochemical characteristics, alkaloids were grouped as sterically bulky (sb) or planar (pg). Docking results revealed strong binding affinities (-6.0 to -13.4 kcal/mol) of the alkaloids against PfDHODH and various strains of PfDHFR while interacting with key residues such as Asp54 and Phe58 in PfDHFR. The pg alkaloids had high binding affinity and preference for the inhibitor binding domain over the flavin mononucleotide (FMN) binding domain in PfDHODH due to size considerations. From the molecular dynamics trajectories, protein-alkaloid complexes were stable throughout the simulation, with supporting evidence from root mean square deviations, root mean square fluctuations, radius of gyration, free binding energies, and other parameters. We report herein that biscryptolepine and cryptomisrine (sb class), as well as cryptolepinone, cryptoheptine, cryptolepine, and neocryptolepine (pg class), are capable of inhibiting PfDHFR effectively in pyrimethamine sensitive and resistant cells. Also, our results show that alkaloids of the pg class can inhibit PfDHODH as FMN decoys, as well as direct enzyme inhibitors, thereby halting crucial protein function.