Machine learning and data-driven approaches are currently being widely used in drug discovery and development due to their potential advantages in decision-making based on the data leveraged from existing sources. Applying these approaches to drug repurposing (DR) studies can identify new relationships between drug molecules, therapeutic targets and diseases that will eventually help in generating new insights for developing novel therapeutics. In the current study, a dataset of 1671 approved drugs is analyzed using a combined approach involving unsupervised Machine Learning (ML) techniques (Principal Component Analysis (PCA) followed by k-means clustering) and Structure-Activity Relationships (SAR) predictions for DR. PCA is applied on all the two dimensional (2D) molecular descriptors of the dataset and the first five Principal Components (PC) were subsequently used to cluster the drugs into nine well separated clusters using k-means algorithm. We further predicted the biological activities for the drug-dataset using the PASS (Predicted Activities Spectra of Substances) tool. These predicted activity values are analyzed systematically to identify repurposable drugs for various diseases. Clustering patterns obtained from k-means showed that every cluster contains subgroups of structurally similar drugs that may or may not have similar therapeutic indications. We hypothesized that such structurally similar but therapeutically different drugs can be repurposed for the native indications of other drugs of the same cluster based on their high predicted biological activities obtained from PASS analysis. In line with this, we identified 66 drugs from the nine clusters which are structurally similar but have different therapeutic uses and can therefore be repurposed for one or more native indications of other drugs of the same cluster. Some of these drugs not only share a common substructure but also bind to the same target and may have a similar mechanism of action, further supporting our hypothesis. Furthermore, based on the analysis of predicted biological activities, we identified 1423 drugs that can be repurposed for 366 new indications against several diseases. In this study, an integrated approach of unsupervised ML and SAR analysis have been used to identify new indications for approved drugs and the study provides novel insights into clustering patterns generated through descriptor level analysis of approved drugs.