After over half a century of chemotherapy research, cancer has remained as one of the most life-threatening diseases to treat. In the present study, a series of phthalazine derivatives as anticancer agent was examined to determine the structural requirement for epidermal growth factor receptor (EGFR) inhibition by three-dimensional quantitative structural activity relationship (3D-QSAR) using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods. Evaluation of 20 compounds (training set) served to establish model, which was validated by evaluation of a set of 08 compounds (test set). The lowest energy conformer of the most active molecule obtained from the systematic search was used as the template structure for alignment of data set. The optimum partial least square analysis (PLS) for CoMFA and CoMSIA models exhibited good leave-one-out cross-validated coefficient (q2) of 0.736 and 0.806, the coefficient of determination (r2) of 0.964 and 0.976 and good predictive power of (r2 pred) of 0.826 and 0.792 respectively. Docking was carried out to identify mode of interaction with EGFR. The final model of QSAR along with information assembled from contour maps and docking study may be used for designing novel phthalazine derivatives as potent anticancer agents.