Marathwada division of Maharashtra is one of the semi-arid regions of India where the agricultural conditions are highly vulnerable to the scanty rain and severe droughts. Over this area, significantly depleting groundwater level and low amount of monsoon rains demands for a good irrigation system for maximum crop cultivation and day-to-day activities. Therefore, this study estimates the spatio-temporal water and vegetation stress to make out the sensitive regions of Marathwada where irrigation network is necessary. The area-specific water requirement is based on the water demand for crops from that particular area. The rate of Evapotranspiration (ET) with potential ET (PET) directly represents the field-specific crop water demands, hence; to understand their relevance we have analyzed the monthly ET and Normalized Difference Vegetation Index (NDVI) by the data acquired from Moderate Resolution Imaging Spectrometer (MODIS) for the period of 2001 to 2017. Water deficiency of particular region is highly dependent on the rainfall vagaries of that area. Therefore, the monthly rainfall product from Tropical Rainfall Measuring Mission (TRMM) was also studied. Station based groundwater data, Soil profile, Land use land cover etc. were the other datasets considered to prioritize the areas for building the irrigation facilities. Study area as a whole, a significant correlation was observed between ET and NDVI. Among the eight districts of Marathwada, Latur, Parbhani Aurangabad and Hingoli were the regions where higher water stress was noticed. On the temporal scale (from last 17 years) maximum water scarcity was noticed over the year 2002-2003 and 2014 -2015. Ensemble bi-decadal analysis of five different drought indices with the aid of IMD observations shows water stress as a proxy variable for drought monitoring. Hence the proven correlation between ET, NDVI and water stress from this study, gives the new interdisciplinary approach to deal with the drought hazards and to priorities the drought-affected area which demands more concern.