A series of 2,3-disubstituted-1,4-naphthoquinone derivatives (1-11) were investigated for their aromatase inhibitory activities. Compounds 1 (2,3-dichloro) and 4 (2-amino-3-chloro) exhibited the most potent activity, affording IC50 values 5.2-fold lower than that of the reference drug, ketoconazole. The QSAR study revealed that mass (Mor04m and H8m), electronegativity (Mor08e), van der Waals volume (G1v) and structural information content index (SIC2) descriptors are influential descriptors governing aromatase inhibitory activity. The 2,3-dihalogen derivatives (1a, 1b and 1c) were predicted to be the most potent modified series, affording predicted pIC50 values in range of 0.550 - 3.582. The prediction suggested that considerably improved activity can be achieved when the 2,3-position of the 1,4-naphthoquinone rings are substituted by halogen atoms with high lipophilicity and electronegativity (i.e., Br, I and F). Notably, the 2,3-diiodo compound 1b exhibited the most potent predicted activity affording the pIC50 value 11.90-fold and 1.03-fold greater than those of its parent compound 1 and the reference drug (letrozole), respectively. Finally, this study provides pertinent knowledge regarding drug design and development and suggests that 1,4-naphthoquinone-based compounds can be further developed as a novel class of aromatase inhibitors.