The halophyte Eutrema salsugineum is naturally distributed in saline-alkali soil and has been proposed as a model plant for understanding plant salt tolerance. As one of the largest and most diverse TF families, basic leucine zipper motif (bZIP) TFs perform robust functions in plant growth and environmental response, however the generalized information of EsbZIP genes and its regulatory role in salt tolerance has not been systematically studied to date. Here, we identified and characterized the bZIP members in E. salsugineum, the sequence feature and phylogeny of EsbZIPs have been exhaustively described. Through the global detection on the transcriptional pattern of EsbZIPs under salt stress, it was found that EsbZIP51 is potentially involved in the positive regulation of salt response. The transgenic plants with heterologous expression of EsbZIP51 exhibited enhanced salt tolerance, as manifested by the healthier growth phenotype and increased capacity in maintaining ion and ROS homeostasis upon salt stress. DNA affinity purification sequencing revealed that a set of candidate genes targeted by EsbZIP51, and functional validation by dual-LUC assays showed EsbZIP51 can specifically bind to the promoter of EsNHX4 and regulates the gene expression, which is required for the modulation of ion balance under salt stress. Together, this study provides insight into the genomic information of EsbZIPs and uncovers a previously uncharacterized functional genes involved in plant salt tolerance.