To study the effects of foliar application of auxin (indole acetic acid) on the morphophysiological and biochemical characteristics of safflower cultivars under water-deficit stress (WDS) condition at the end of the growing season, an experiment was performed using split-plot factorial in the form of randomized complete block design with three replicates during the 2018–2019 and 2019–2020 crop seasons. The main factor of this experiment was water-deficit stress in two levels, i.e., normal irrigation (control) and irrigation cut-off at flowering stage, and two sub-factors include safflower cultivars (Golmehr and Goldasht) and foliar application of auxin in two levels, i.e., no application and applying 4 g.L−1 auxin. Water stress decreased bush heights, grain weight, grain yield, biological yield, harvest index, SPAD index, contents of oil, palmitic acid, linoleic acid, and oleic acid and increased proline content and activities of antioxidant enzymes such as catalase and peroxidase. In comparison with the Golmehr cultivar, the Goldasht cultivar had a higher number of grains (13.27%), grain yield (32.42%), and biological yield (34.29%). Higher bush height (15%), oil percent (9.58%), linoleic acid (30.76%), and oleic acid content (19.59%) were observed in Golmehr cultivar. Under WDS, the activities of antioxidant enzymes and proline in the two cultivars did not change significantly; however, under WDS, meanwhile, Goldasht cultivar showed higher catalase (12%) and peroxidase (13.5%) activities and proline (11.04%). Since using auxin alleviated the side effects of WDS through increasing SPAD index (2.51%), proline content (17.93%), and activities of catalase (30.53%) and peroxidase (14.72%) enzymes, auxin application can be recommended for alleviating the effects of WDS.