Two-dimensional quantitative structure−activity relationship (2D-QSAR) models are useful in understanding how chemical structure is related to the biological activity of natural and synthetic chemicals. Also, they could be usefully employed for designing newer and better therapeutics. A 2D-QSAR study was performed for 52 compounds of a series of thiophenyl quinolines and α-asarone derivatives as potential hypocholesterolemic inhibitors using different types of physicochemical descriptors, which correlated significantly with the activity. Linear QSAR models were developed using multiple linear regression, where the genetic algorithm (genetic function approximation technique) was adopted for selecting the most appropriate descriptors. The results are discussed on the basis of regression data and the cross-validation technique. Model A is the best 2D-QSAR model describing the inhibition efficiency of HMG-CoA reductase with cross-validated squared correlation coefficient (Q 2 = 0.700) and the squared correlation coefficient (R 2 = 0.752), which is able to describe 70% of the variance in the experimental activity. The good agreement between the experimental and the predicted values of pIC50 (micromoles per litre) (R = 0.876) confirms the reliability and the predictability of the proposed model. The results obtained from the present QSAR study explained the importance of the electronic, structural, spatial, and electrotopological descriptors in enhancing the biological activity of the investigated inhibitors.