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Inclusion of drought tolerant, low input crops such as safflower (Carthamus tinctorius L.) is one of the strategies to extend the life, of fast declining Ogallala Aquifer in the Southern High Plains (SHP). Crop modeling is a viable option to simulate safflower water footprints in different climatic scenarios to assess its feasibility in optimization of water use in the SHP. Such progress would join corollary efforts to improve irrigation management practices of safflower for increased water productivity. The primary objective of the study was to calibrate the CROPGRO model for improved ability to simulate water balance, evapotranspiration (ET) and water use efficiency (WUE) of spring safflower. The model was calibrated based on soil water extraction data from P18311 cultivar in an experiment conducted during 2013 and 2014 at Clovis, NM. The observed data from other two cultivars, 990L and Nutrisaff, were used to evaluate the model. The model was able to simulate total above ground biomass of safflower in a reasonable fashion. The optimal prediction of soil water content, water balance and seed yield of safflower led to excellent ET and WUE simulations with root mean square error of 34mm and 0.6 kg ha(-1) mm(-1), respectively. The satisfactory performance of the model for an independent data demonstrates that the CROPGRO model is capable of predicting water use of spring safflower in semi-arid regions of the SHP; however, site-specific calibrations based on weather, especially soil and rooting inputs may be needed in different regions.