Dipeptidyl peptidase 4 (DPP-4) inhibition is a promising therapy for type 2 diabetes. Inhibition of DPP-4 limits the breakdown of glucagon-like peptide 1 (GLP-1), hence increasing functional GLP-1 levels. This boosts the secretion of insulin and decreases glucagon release, resulting in a reduction in blood sugar levels. In an effort to discover the chemical and structural prerequisite for DPP-4 inhibition, computational investigations involving Quantitative Structural–Activity Relationship (QSAR) studies were performed on 63 compounds with pIC50 values ranging from 7.0 to 9.744. With a good R2 (0.716) and cross-validated correlation coefficient value Q2 LOO (0.6120), a model was created that quantitatively describes the relationship. The regression approach systematically gives that the topological state of an atom, the presence of CF3 at the second position of the triazole ring (knotpv), the polarizabilities (RDF15p), the atomic masses (MATS3M), the heteroatom, and the valence distribution had a significant effect on DPP-4 inhibition (Chiv4pc). In addition, docking results revealed favorable contacts between triazolopiperazine analogues and catalytically significant amino acid residues, including HIS740, SER630, ASN710, and GLU205. Comparing the interactions of the most active compound 4 to those of the standard Sitagliptin reveals comparable binding energies. The study demonstrates that substituting CF3 at the second position of the triazole nucleus and incorporating polarity-altering groups are advantageous for inhibiting the DPP-4 enzyme.