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Cholesterol biosynthesis is a critical pathway in cellular metabolism, with 3-hydroxy-3-methylglutaryl coenzyme-A reductase (HMGR) catalyzing its committed step. The inhibition of HMGR has been widely explored as a therapeutic target for managing hypercholesterolemia, and statins are the most commonly used competitive inhibitors. However, the search for novel, natural inhibitors of HMGR is still a vital area of research, especially in light of the adverse effects of the prolonged use of statins. In this study, the potential of 84 phytochemicals isolated from two species of Cochlospermum (C. planchonii and C. tinctorium) reported in the literature, was investigated as novel inhibitors of human HMGR using molecular docking techniques. The phytochemicals were screened for their drug-likeness and ADMET properties in accordance with Lipinski rule of five, and 32 of them were docked against the HMG-binding portion within the active site of the enzyme, together with its native ligand and 6 known statins serving as control ligands. The docking results revealed that 10 of the compounds exhibited strong binding affinities and interactions with the HMG-binding pocket of the enzyme, comparable to or exceeding those of the control ligands. This evidence strongly suggests their potential as effective inhibitors of HMGR. For the first time, the findings from this research identify and directly implicate the specific bioactive compounds of C. planchonii and C. tinctorium capable of exerting cholesterol-lowering effects in humans, while validating previously reported studies on the efficacy of these plants extracts used in West African traditional medicine to manage dyslipidemia, among a host of other ailments. The compounds identified may serve as promising drug candidates which can be further optimized and developed as novel, natural inhibitors of HMGR. Keywords: statins; phytochemicals; cochlospermum; hypercholesterolemia; molecular docking.