Pancreatic lipase is a digestive enzyme involved in the hydrolysis of dietary fats. Orlistat, a potent pancreatic lipase inhibitor, is widely prescribed for long-term obesity treatment. Nevertheless, orlistat is reported for severe adverse effects including hepatotoxicity and pancreatitis. In the present study, a novel series of 11 benzyloxy substituted indole glyoxylamides were designed, synthesized and evaluated for pancreatic lipase inhibitory activity. Three analogues, , and , exhibited potent activity (IC ≤ 2.5 µM), with exhibiting a potent IC of 1.68 µM comparable to orlistat (IC = 0.99 µM). Further, exhibited reversible competitive inhibition with an inhibitory constant value of 0.98 μM. Molecular docking of these analogues was in agreement with results, wherein the MolDock scores exhibited significant correlation with their inhibitory activity (Pearson's  = 0.7122). A 50 ns molecular dynamics simulation of pancreatic lipase complex confirmed the role of extended alkyl interactions along with π-π stacking and π-cation interactions, in stabilizing the ligand (Maximum RMSD ≈ 3 Å) in the active site. Gastro-intestinal absorption and toxicity prediction of the three potent analogues highlighted the suitability of for experiments. at a dose of 20 mg/kg exhibited anti-obesity efficacy comparable to orlistat (10 mg/kg), wherein the serum triglycerides were found to be 94.95 and 83.85 mg/dL, respectively. Further, faecal triglyceride quantification indicated to act through pancreatic lipase inhibition similar to orlistat. The present study identified a novel pancreatic lipase inhibitory benzyloxy substituted bis(indolyl) glyoxylamide with promising anti-obesity activity.Communicated by Ramaswamy H. Sarma.