Astragalus mongholicus, an important medicinal plant species, exhibits low tolerance to high-salt environments, which restricts its growth in saline-alkaline areas. Understanding its salt-tolerance mechanisms is crucial for overcoming the technical challenges of industrialized cultivation in these regions. However, studies on the salt-tolerance mechanisms of Astragalus mongholicus are limited. This study examines two Astragalus mongholicus germplasms with distinct differences in salt tolerance (LQ: salt-tolerant, DT: salt-sensitive), and investigates their physiological adaptations and molecular mechanisms under salt stress (200 mmol/L NaCl) using an integrated analysis of morphology, physiology, metabolomics, and transcriptomics. Specifically, LQ showed smaller reductions in plant height, root length, root thickness, and fresh weight (29.0%, 5.0%, 2.8%, and 22.3%, respectively), compared to DT, which exhibited larger reductions (42.9%, 44.9%, 46.3%, and 41.4%, respectively). The results indicated that the salt-tolerant germplasm (LQ) enhanced antioxidant enzyme activities in response to salt stress, including SOD, POD, and CAT, and accumulating osmoregulatory substances. In LQ, the activities of SOD, POD, and CAT increased by 22.8%, 10.9%, and 8.8%, respectively, significantly higher than those of DT, which showed increases of 2.9%, 8.5%, and 1.4% in SOD, POD, and CAT activities, respectively. The contents of soluble sugar and protein in LQ increased by 2-fold and 16.9%, respectively, compared to 67.0% and 18.8% increases in DT. Additionally, the levels of MDA, H2O2, and OFR in LQ showed smaller increases (14.7%, 41.0%, and 13.6%, respectively), compared to the larger increases observed in DT (58.0%, 51.2%, and 18.6%), indicating a reduced level of oxidative damage in LQ and enhanced tolerance to salt stress. Combined transcriptomic and metabolomic analyses revealed that 3510 differentially expressed genes (DEGs) and 882 differentially expressed metabolites (DAMs) were identified in the leaves of salt-tolerant germplasm LQ under salt stress, whereas the sensitive germplasm DT had 1632 DEGs and 797 DAMs, respectively. Differential genes and metabolites were involved in metabolic pathways such as flavonoid biosynthesis, isoquinoline alkaloid synthesis, and phenylalanine metabolism. In particular, LQ alleviated salt stress damage and enhanced salt tolerance by increasing oxidase activities in its flavonoid and phenylalanine metabolic pathways and regulating the expression of key genes and enzymes. This study provides valuable insights and empirical data to support the selection of appropriate Astragalus mongholicus germplasms for saline regions and the development of improved cultivars.