The Semliki Forest Virus (SFV) is an RNA virus with a positive-strand that belongs to the Togaviridae family's Alphavirus genus. An epidemic was observed among French troops stationed in the Central African Republic, most likely caused by the SFV virus. The two transmembrane proteins El and E2 and the peripheral protein E3 make up the viral spike protein. The virus binds to the host cell and is internalized via endocytosis; endosome acidification causes the E1/E2 heterodimer to dissociate and the E1 subunits to trimerize. Lupenone was evaluated against the E1 spike protein of SFV in this study based on state-of-the-art cheminformatics approaches, including molecular docking, molecular dynamics simulation, and binding free energy calculation. The molecular docking study envisaged major interactions of Lupenone with binding cavity residues involved non-bonded van der Waal's and Pi-alkyl interactions. Molecular dynamic simulation of a time scale 200 ns corroborated interaction pattern with molecular docking studies between Lupenone and E1 spike protein. Nevertheless, Lupenone intearcation with the E1 spike protein conforming into a stable complex substantiated by free energy landscape (FEL), PCA analysis. Free energy decomposition of the binding cavity resdiues of E1 spike protein also ensured the efficient non-bonded van der Waal's interaction contributing most energy to interact with the Lupenone. Therefore, Lupenone interacted strongly at the active site conforming into higher structural stability throughout the dynamic evolution of the complex. Thus, this study perhaps comprehend the efficiency of Lupenone as lead molecule against SFV E1 spike protein for future therapeutic purpose.