Salicylaldehyde benzoylhydrazone (H2sb) has a variety of biological activities including anticancer activity. The Cu(II) complexes of H2sbs possess enhanced anticancer activity as compared with their free ligands. A quantitative structure–activity relationship (QSAR) analysis was performed on a series of H2sb ligands and their corresponding Cu(II) complexes to capture the structural requirements that are responsible for the bioactivity. The predictive QSAR models were developed using statistical techniques such as multiple linear regression (MLR) and principal component regression analysis (PCRA). We used different combinations of various descriptors such as a physicochemical descriptor, electrotopological state atom (ETSA) indices, and descriptors derived from density functional theory (DFT) calculations. The DFT-derived descriptors used for QSAR analysis are HOMO and LUMO energies, atomic charges, chemical potential, and hardness. Our developed models showed the importance of the lipophilicity index (ClogP), ETSA indices, and atomic charges for anticancer activities of the H2sb analogs and their Cu(II) complexes. In addition, our MLR models revealed that, while the global lipophilicity index and hardness are important for anticancer activity of H2sb ligands, chemical potential and HOMO energy are important for the anticancer activity of Cu(II) complexes.