AIM: This study investigates the anti-proliferative potential and possible molecular mechanisms of 3-(2-furoyl)-indole derivatives against HepG2. METHOD: Identified hit compounds (4a, 4b, 4c) using MTT screening, were further investigated for their efficacy and mechanism of action through FACS studies, in-silico molecular docking, molecular dynamics (MD) simulations, and label-free quantitative proteome and ADMET prediction. RESULTS: Lead compound 4a, showed IC50 of 27 µM against HepG2 cells and a binding score of -8.077 kcal/mol against IGF-1 R (PDB ID: 5XFS) and formed a stable complex 100 ns. Proteomic study revealed significant downregulation of the IGF-1 R downstream signaling molecules and showed minimal toxicity and favorable drug-like properties. CONCLUSION: These findings suggest that 4a is a promising IGF-1 R inhibitor and potential drug candidate against drug resistance hepatocellular carcinoma (HCC).