Saline-alkaline aquaculture plays a crucial role in the ecological restoration of saline soils, yet high water salinity can significantly restrict the growth of cultured organisms. The Chinese mitten crab (Eriocheir sinensis) is typically farmed in freshwater, to evaluate the effects of salinity stress on these crabs, this study conducted laboratory aquaculture experiments at salinities of ≤ 0.5 (freshwater), 6, 12, and 18 ‰. Regular data on crab survival and growth were collected over 35 days. Subsequently, tissues including the eyestalk, posterior gill, hepatopancreas, and ovary were sampled from crabs in both the freshwater control group and the 18 ‰ salinity treatment group for transcriptional and metabolomic analysis. The omics data were used to ascertain the physiological mode of action (pMoA) affected by salinity in the crabs. A dynamic energy budget toxicokinetic-toxicodynamic (DEB-TKTD) model was built based on these pMoAs to predict the life history traits of crabs across different salinities, including survival, growth, and reproduction. The omics results indicated that at 18 ‰, the osmoregulatory capacity and oxidative stress resistance were enhanced, and vitellogenin synthesis was stimulated. This suggests that the two pMoAs involved increasing maintenance costs and reallocating energy between soma and reproduction. DEB-TKTD model predictions fit well with the observed data, with high R