Background The emergence of Multi-drug resistant tuberculosis in pandemic proportions throughout the world and the paucity of novel therapeutics for tuberculosis have re-iterated the need to accelerate the discovery of novel molecules with anti-tubercular activity. Though high-throughput screens for anti-tubercular activity are available, they are expensive, tedious and time-consuming to be performed on large scales. Thus, there remains an unmet need to prioritize the molecules that are taken up for biological screens to save on cost and time. Computational methods including Machine Learning have been widely employed to build classifiers for high-throughput virtual screens to prioritize molecules for further analysis. The availability of datasets based on high-throughput biological screens or assays in public domain makes computational methods a plausible proposition for building predictive models. In addition, this approach would save significantly on the cost, effort and time required to run high throughput screens. Results We show that by using four supervised state-of-the-art classifiers (SMO, Random Forest, Naive Bayes and J48) we are able to generate in-silico predictive models on an extremely imbalanced (minority class ratio: 0.6%) large dataset of anti-tubercular molecules with reasonable AROC (0.6-0.75) and BCR (60-66%) values. Moreover, these models are able to provide 3-4 fold enrichment over random selection. Conclusions In the present study, we have used the data from in-vitro screens for anti-tubercular activity from a high-throughput screen available in public domain to build highly accurate classifiers based on molecular descriptors of the molecules. We show that Machine Learning tools can be used to build highly effective predictive models for virtual high-throughput screens to prioritize molecules from large molecular libraries.