Drought is increasing prevalently, mostly due to global warming, and harmful effects associated with drought stress include a reduction in the developmental phases of the plant life cycle. Drought stress affects vital metabolic processes in plants such as transpiration, photosynthesis and respiration. The other physiological and cellular processes like protein denaturation and aggregation are also affected by drought. Drought stress severely affects the floral industry by reducing the yield of flowers and among them is chrysanthemum (Dendranthema grandiflorum). In this study, we determined the critical signaling pathways, tolerance mechanism and homeostatic maintenance to drought stress in chrysanthemum. We compared the proteome of chrysanthemum leaves under drought stress. Among 250 proteins on 2DE gels, 30 protein spots were differentially expressed. These proteins were involved in major signaling pathways including, stress response, flower development and other secondary metabolism like physiological transport, circadian rhythm, gene regulation, DNA synthesis and protein ubiquitination. A reduction in a biomass, flower development, photosynthesis, transpiration, stomatal conductance, PSII yield and stomatal index was also observed in our results. Moreover, the stress markers and leaf water potential were also analyzed to depict the level of stress tolerance in chrysanthemum. Our data suggested that chrysanthemum plants developed reactive oxygen species and revealed signaling pathways to cope with drought stress. These results, thus, provide crucial information about how chrysanthemum plants respond to drought stress to maintain homeostasis. © 2020 Scandinavian Plant Physiology Society