Quantitative structure–activity relationship (QSAR) studies were performed on quinazolinone analogues for prediction of antihypertensive activity. The best significant 2D-QSAR model having r2 = 0.8118 and pred_r2 = 0.7428 was developed by stepwise-partial least square method. k-nearest neighbor molecular field analysis was used to construct the best 3D-QSAR model, showing good correlative and predictive capabilities in terms of q2 = 0.7388 and pred_r2 = 0.6983. Results reveal that the 2D-QSAR studies signify positive contribution of SssOE index and SsCH3 count towards the biological activity. The results have showed that electronegative groups are necessary for activity and halogen, bulky, less bulky groups in quinazolinones nucleus enhanced the biological activity. The information rendered by 2D- and 3D-QSAR models may lead to a better understanding of structural requirements of substituted quinazolinones derivatives and also aid in designing novel potent antihypertensive molecules.