Parasitic diseases are some of the most lethal and pervasive infections globally, causing millions of cases of morbidity and mortality annually.Plasmodium falciparum is the predominant vector-borne pathogen, resulting in 0.5 million fatalities annually.Malaria, caused by Plasmodium falciparum, continues to be a significant worldwide health issue, requiring the development of novel treatment medicines to address increasing medication resistance. This study undertakes a focused in silico screening of phytochemicals derived from Centella asiatica against dihydrofolate reductase-thymidylate synthase (PfDHFR-TS), represented by PDB ID: 3BWK. This work investigated molecular modeling to clarify the probable mechanism of its anti-malarial activity through the suppression of falciparum proteins. Campesterol exhibits a maximal binding affinity (docking score: −8.6 Kcal/mol) for FP-2 from Plasmodium falciparum, as determined by our molecular docking investigation of 30 bioactive compounds from Centella asiatica. However, Ursolic acid and rutin also showed potential activity with significant docking scores (−8.5 and 8.4 Kcal/mol). Campesterol, recognized as a possible inhibitor of falciparum, offers a viable pathway for the treatment of malaria, necessitating additional investigation into its therapeutic use. This research provides significant insights into the molecular interactions between phytochemicals, facilitating innovative and successful strategies for malaria treatment. Our research indicates that polyphenols derived from Centella asiatica exhibit significant pharmacological potential against several biological targets.