Drought stress is one of the most important stresses in plants. The important role of calcium signal as a second messenger in alleviating drought stress is still unclear. We used tobacco as test material to simulate drought stress with 20 % PEG concentration. Physiological and transcriptome techniques were used to study how the model plant tobacco protects itself from drought stress by examining the mechanism used by exogenous calcium ions to respond to the antioxidant and hormone signals that indicate drought stress. Exogenous calcium was shown to increase the levels of expression of the proteins CDPK, CBL/CIPK and AQPs that respond to signaling by calcium under drought stress. The cis-acting elements of the promoters of the genes related to signals primarily focused on hormone and drought-related elements, which suggests that the exogenous calcium may mediate the transduction of hormone signals in response to drought stress. The results of physiological and transcriptional data showed that oxidative damage occurred in the tobacco leaves under drought stress. Under drought stress, exogenous calcium can enhance the activities of SOD (4.75 %), POD (42.33 %) and APX (512.43 %), up-regulate the expression of the genes that encode antioxidant enzymes to eliminate excessive reactive oxygen species (ROS), and alleviate the oxidative damage to tobacco leaves under drought stress. The calcium produced during drought stress increased the content of auxin (IAA), decreased that of abscisic acid (ABA) and downstream gene expression, and prevented excessive amplification of the ABA signal. Exogenous calcium enhanced the crosstalk between cytokinin, gibberellin and ABA signals.In summary, exogenous calcium can stimulate the synergistic effect of calcium and hormone signals and the antioxidant system, eliminate ROS, improve the crosstalk between plant hormones, and improve the drought resistance of tobacco.