Background/Objectives: HMG-CoA reductase is an enzyme that regulates the initial stage of cholesterol synthesis, and its inhibitors are widely used in the treatment of cardiovascular diseases. Methods: We have created a set of quantitative structure-activity relationship (QSAR) models for human HMG-CoA reductase inhibitors using nested cross-validation as the primary validation method. To develop the QSAR models, we employed various machine learning regression algorithms, feature selection methods, and fingerprints or descriptor datasets. Results: We built and evaluated a total of 300 models, selecting 21 that demonstrated good performance (coefficient of determination, R2 ≥ 0.70 or concordance correlation coefficient, CCC ≥ 0.85). Six of these top-performing models met both performance criteria and were used to construct five ensemble models. We identified the descriptors most important in explaining HMG-CoA inhibition for each of the six best-performing models. We used the top models to search through over 220,000 chemical compounds from a large database (ZINC 15) for potential new inhibitors. Only a small fraction (237 out of approximately 220,000 compounds) had reliable predictions with mean pIC50 values ≥ 8 (IC50 values ≤ 10 nM). Our svm-based ensemble model predicted IC50 values < 10 nM for roughly 0.08% of the screened compounds. We have also illustrated the potential applications of these QSAR models in understanding the cholesterol-lowering activities of herbal extracts, such as those reported for an extract prepared from the Iris × germanica rhizome. Conclusions: Our QSAR models can accurately predict human HMG-CoA reductase inhibitors, having the potential to accelerate the discovery of novel cholesterol-lowering agents and may also be applied to understand the mechanisms underlying the reported cholesterol-lowering activities of herbal extracts.