Muhammad Tahir Aqeel,1 Nisar ur-Rahman,1 Arif-ullah Khan,2 Zaman Ashraf,3 Muhammad Latif,4 Hummera Rafique,5 Usman Rasheed1 1Department of Pharmacy, COMSATS Institute of Information Technology Abbottabad, Abbottabad, Pakistan; 2Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad, Pakistan; 3Department of Chemistry, Allama Iqbal Open University, Islamabad, Pakistan; 4College of Medicine, Centre for Genetics and Inherited Diseases (CGID), Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia; 5Department of Chemistry, University of Gujrat, Gujrat, Pakistan Background: Hyperlipidemia is a worth-mentioning risk factor in quickly expanding cardiovascular diseases, including myocardial infarction and, furthermore, in stroke. Methods: The present work describes the synthesis of phenolic derivatives 4a–e and 6a–c with the aim of developing antihyperlipidemic agents. The structures of the synthesized compounds were confirmed by spectroscopic data. The in silico docking studies were performed against human 3-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA) reductase enzyme (PDB ID: 1HWK), and it was observed that compounds 4a and 6a exhibited maximum binding affinity with target protein having binding energies −8.3 and −7.9 kcal, respectively. Results: Compound 4a interacts with amino acids Val805 with distance 1.89 Å and Met656, Thr558, and Glu559 with bonding distances 2.96, 2.70, and 2.20 Å, respectively. The in vivo antihyperlipidemic activity results revealed that compound 4a indicated minimum weight increment, ie, 20% compared with 35% weight increment with standard drug atorvastatin during 6 weeks of treatment. Moreover, increment in high-density lipoprotein cholesterol and decrease in total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels were more prominent in case of 4a compared to atorvastatin with P<0.05. The synthesized compounds were nontoxic and well tolerated because none of the mice were found to suffer from any kind of morbidity and death during 6 weeks of dosing. Conclusion: Based on our pharmacological evaluation, we may propose that compound 4a may act as a lead structure for the design and development of more potent antihyperlipidemic drugs. Keywords: phenolic derivatives, synthesis, antihyperlipidemic, in silico docking, HMG CoA reductase, atorvastatin