Drought is one of the major environmental stress that adversely affect the growth and development of oil seed plant, safflower. There is a limited knowledge on proteomic responses to support physiological, biochemical changes in how safflowers can regulate growth and metabolism under drought conditions and followed by re-watering. The changes in morphological, physiological, biochemical and proteomics of safflower genotypes (Carthamus tinctorius L.; Remzibey-05 and Linas, tolerant and sensitive cultivars, respectively, and C. oxyacantha M. Bieb., wild type) after exposure to drought and followed by re-watering have been examined. Drought negatively affected the shoot weight, water content, chlorophyll fluorescence, and biochemical parameters, including photosynthetic pigment, proline, MDA, and H2O2 contents and antioxidant enzyme activities in all genotypes, while the re-watering period allowed Remzibey-05 to recover, and it even provided the wild type completely recovered (approximately 100%). A total of 72 protein spots were observed as differently accumulated under treatments. The identified proteins were mainly involved in photosynthesis and carbohydrate, protein, defense, and energy metabolisms. Protein accumulation related to these metabolisms in Remzibey-05 were decreased under drought, while increased following re-watering. However, sensitive cultivar, Linas, could not exhibit an effective performance under drought and recovery when compared with other safflower genotypes.