Traditional drug discovery methods are target-based, time- and resource-intensive, and require a lot of resources for the initial hit molecule identification. Phenotype-based drug screening requires differential gene expression data of a large number of molecules for different combinations of cell-line, time point and dosage. Experimentally obtaining gene expression data for all these combinations is again a heavily resource-intensive process. The technical challenge in conventional methods that use prediction models is that they depend largely on the data processing and representation. The disclosure herein generally relates to drug-like molecule screening, and, more particularly, to a method and system for gene expression and machine learning-based drug screening. The embodiment, thus, provides a mechanism of a small molecule-induced gene expression prediction based on machine learning models. Moreover, the embodiments herein further provide a mechanism of screening of drug-like molecules using the machine learning model(s).