Sirtuin 2 is a key enzyme in gene expression regulation that is often associated with tumor proliferation control and therefore is a relevant anticancer drug target. Anilinobenzamide derivatives have been discussed as selective sirtuin 2 inhibitors and can be developed further. In the present study, hologram and three-dimensional quantitative structure–activity relationship (HQSAR and 3D-QSAR) analyses were employed for determining structural contributions of a compound series containing human sirtuin-2-selective inhibitors that were then correlated with structural data from the literature. The final QSAR models were robust and predictive according to statistical validation (q2 and r2pred values higher than 0.85 and 0.75, respectively) and could be employed further to generate fragment contribution and contour maps. 3D-QSAR models together with information about the chemical properties of sirtuin 2 inhibitors can be useful for designing novel bioactive ligands.