This review explores the therapeutic promise of natural compounds in modulating 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), a key enzyme in cholesterol synthesis. HMGCR dysregulation is implicated in dyslipidemia, cardiovascular disease, and cancer, conditions linked to oxidative stress. While statins inhibit HMGCR, their side effects necessitate exploring alternatives. The review highlights various natural compounds-flavonoids, phenolic acids, stilbenes, and herbal formulations-with HMGCR-modulating and antioxidant capabilities. In vitro and in vivo studies suggest these compounds offer a promising avenue for treating HMGCR-related conditions. Synergistic effects are observed when combining natural products with statins, hinting at combination therapies that could lower statin dosages and reduce adverse effects. Natural HMGCR modulators hold therapeutic promise but face hurdles like limited in vivo data, regulatory issues, variability in composition, potential drug interactions, and safety concerns. Future research must prioritize comprehensive mechanistic studies, standardized preparations, and well-designed clinical trials. Overcoming these challenges through rigorous science is essential for integrating natural HMGCR modulators into clinical practice and improving patient outcomes in a safe and effective manner. Specifically, clinical trials should consider combination therapies and comparison with standard treatments like statins. More research is also needed on optimal dosages and treatment regimens.