The relationship between the topological indices and the Neutral Endopeptidase (NEP) inhibitory activity and Angiotensin-Converting Enzyme (ACE) inhibitory activity of mercaptoacyldipeptides has been investigated. Three topological indices — the Wiener index (a distance-based topological index), the molecular connectivity index (an adjacency-based topological index), and the eccentric connectivity index (an adjacency-cum-distance-based topological index), were presently used for investigation. A data set comprising 39 differently substituted mercaptoacyldipeptides was selected for the present study. The values of the Wiener index, molecular connectivity index, and eccentric connectivity index for each of the 39 compounds comprising the data set were computed using an in-house computer program. Resultant data were analyzed and suitable models were developed after identification of the active ranges. Subsequently, a biological activity was assigned to each compound using these models, and the biological activity was then compared with the reported NEP and ACE inhibitory activity of each compound. Accuracy of prediction up to a maximum of ~91% was obtained using these models.