In view of the emergence of drug-resistant strains of Plasmodium falciparum, there is an urgent need for the development of new effective antimalarial agents to mitigate the issue of drug resistance. In this study, a series of lupeol (2) and betulin (3) derivatives were synthesised, characterised and evaluated for their antimalarial activity against the P. falciparum FCR3 strain. Eight compounds, including lupenone (1), displayed good anti-plasmodial potency with IC50 values ranging from 0.03-9.9 µM. Moreover, in vitro results showed that compound 1 and derivatives 4a and 4b were the most active compounds with potent inhibitory activity of (0.3 ± 0.3, 0.03 ± 0.05 and 0.7 ± 0.8 μM), respectively, compared to the reference drugs artemisinin and chloroquine (0.7 ± 0.3 and 10.3 ± 2.9 μM), respectively. Furthermore, molecular docking analysis of these compounds revealed good affinity to the binding site of the P. falciparum protein of the PfATP6 with a binding affinity between -9.8 and -8.4 kcal mol-1 via multiple hydrophobic interactions with the amino acid of the PfATP6 protein. The results showed hydrogen bonds and various hydrophobic interactions between the studied compounds and the amino acid of the PfATP6 protein, such as ASN1039, VAL984, ILE981 and ILE1041. Therefore, these compounds could be promising lead structures for further validation as potential candidates in developing new antimalarial drugs.