Tomato spotted wilt virus (TSWV), transmitted by small insects known as thrips, is one of the major threats to tomato productivity across the globe. In addition to tomato, this virus infects more than 1000 other plants belonging to 85 families and is a cause of serious concern. Very little, however, is known about the molecular mechanim of TSWV induced signaling in plants. Here, we used a TMT-based quantitative proteome analysis to investigate the protein profiles of tomato leaves of two cultivars (cv 2621and 2689; susceptible and resistant respectively to TSWV infection) following TSWV inoculation. This approach resulted in the identification of 5112 proteins of which 1022 showed significant changes in response to TSWV. While the proteome of resistant cultivar majorly remain unaltered, proteome of susceptible cultivar showed distint differences following TSWV infection. TSWV modulated proteins in tomato included those with functions previously implicated in plant defence incuding secondary metabolism, ROS detoxification, MAP kinase signaling, Calcium signaling and jasmonate biosynthesis, among others. Taken together, these results provide new insights into the TSWV induced signaling in tomato leaves and may be useful in future to manage this deadly disease of plants.