Salinization is one of the major factors that threaten the existence of plants worldwide. Populus euphratica has been deemed to be a promising candidate for stress response research because of its high capacity to tolerate extreme salt stress. We carried out a genome-wide transcriptome analysis to identify the differentially expressed genes (DEGs) response to salt shock and elucidate the early salt tolerance mechanisms in P. euphratica. Both hierarchical clustering and DEG analysis demonstrated a predominant variation from time-course rather than NaCl intensity within 24 hours salt shock. Among the identified 1,678 salt-responsive DEGs, 74.1% (1,244) have not been reported before. We further created an integrated regulatory gene network of the salt response in P. euphratica by combining DEGs, transcription factors (TFs), Helitrons, miRNAs and their targets. The prominent pathways in this network are plant hormone transduction, starch and sucrose metabolism, RNA transport, protein processing in endoplasmic reticulum, etc. In addition, the network indicates calcium-related genes play key roles in P. euphratica response to salt shock. These results illustrated an overview of the systematic molecular response in P. euphratica under different intensities of salt shock and revealed the complex regulatory mechanism.