In the scenario of global climate change, understanding how plants respond to drought is critical for developing future crops that face restricted water resources. This present study focuses on the role of WRKY transcription factors on drought tolerance in tomato, Solanum lycopersicum L., which is a significant vegetable crop. WRKY transcription factors are a group of proteins that regulate a wild range of growth and developmental processes in plants such as seed germination and dormancy and the stress response. These transcription factors are defined by the presence of a DNA-binding domain, namely, the WRKY domain. It is well-known that WRKY transcription factors can interact with a variety of proteins and therefore control downstream activities. It aims to simulate the effect of curcumin, a bioactive compound with regulatory capacity, on the protein–protein interaction events by WRKY transcription factors with an emphasis on drought stress. It was found that curcumin binds to WRKY with an energy of −11.43 kcal/mol with inhibitory concentration (Ki) 0.12 mM and has the potential to improve fruit quality and reinforce drought tolerance of S. lycopersicum, according to the results based on bioinformatics tools. The root means square deviation (RMSD) of the C-α, the backbone of 2AYD with ligand coupled complex, displayed a very stable structure with just a little variation of 1.89 Å. MD simulation trajectory of Cα atoms of 2AYD bound to Curcumin revealed more un-ordered orientation in PC1 and PC10 modes and more toward negative correlation from the initial 400 frames during PCA. Establishing the binding energies of the ligand–target interaction is essential in order to characterize the compound’s binding affinity to the drought transcription factor. We think we have identified a phyto-agent called curcumin that has the potential to enhance the drought tolerance. Compared to the part of the mismatch repair-base technique that can be used to fix drought related genes, curcumin performed better in a drop-in crop yield over time, and it was suggested that curcumin is a potential candidate factor for improving drought tolerance in tomatoes, and it needs future validation by experiments in laboratory and field.