In this study, a series of coumarin-indole hybrids have been synthesized and evaluated for their lipid lowering activity. Preliminary biological screening of synthesized compounds was undertaken in an in vitro model of HMG-CoA reductase enzyme and the activity was confirmed in Triton WR-1339 induced hyperlipidemic rats. Among the hybrids, compound 26 was found to be the most persuasive as it significantly reduced the serum and hepatic lipid profile in an HFD-fed hyperlipidemic rat model. The mechanism of action seems to be associated with the regulation of HMG-CoA reductase activity in liver,which is in good agreement with its binding mode studies. Compound 26 exhibited favorable pharmacokinetic behavior for its oral administration, which underscores the potential of this template as a new class of hypolipidemic agents.