Quantitative structure–activity relationship studies conducted on forty-five (45) derivatives of 2-anilino 4-amino substituted quinazolines as malaria inhibitors to determine the structures responsible for their antimalarial properties and design novel derivatives with improved activities. The molecular descriptors generated were selected to develop the theoretical model using the genetic approximation component of the material studio. The developed model found to be a function of ATSC8c, GATS8i, SpMin1_Bhi, JGI10, and TDB6u descriptors, shows excellent statistical parameters (R² = 0.7913, R²_adj = 0.7553, Q²cv = 0.7112, LOF = 0.2125, and R²_pred = 0.7650). The mean effect (MF) analysis revealed the descriptor SpMin1_Bhi, as the most influential by its largest percentage contribution (54%) to the developed model. The descriptor decodes the information on the first ionization potentials and was found to have positive MF. Hence, activity increases with increases the descriptor value. Structural modifications of the template (compound 13; pEC₅₀ = 7.387) using electron-withdrawing groups increases the descriptor value (first ionization potentials) of the template, which by extension increases the antimalarial activity lead to the design of ten (10) novel theoretical derivatives with improve antimalarial activities. Compound 3, N4-(3-bromo-5-fluorobenzyl)-N2-(4-fluorophenyl)-6,7-dimethoxyquinazoline-2,4-diamine was found to have the highest antimalarial activities among all the designed derivatives (pEC₅₀ = 8.0515).