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 mechanism of TSWV induced signaling in plants. Here, we used a tandem mass tags (TMT)-based quantitative proteome approach to investigate the protein profiles of tomato leaves of two cultivars (cv 2621 and 2689; susceptible and resistant to TSWV infection, respectively) 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 remains unaltered, the proteome of susceptible cultivar showed distinct differences following TSWV inoculation. TSWV modulated proteins in tomato included those with functions previously implicated in plant defense including secondary metabolism, reactive oxygen species (ROS) detoxification, mitogen-activated protein (MAP) kinase signaling, calcium signaling and jasmonate biosynthesis, among others. Taken together, results reported here provide new insights into the TSWV induced signaling in tomato leaves and may be useful in the future to manage this deadly disease of plants.