The molecular coordination between the central nervous system and peripheral organs is fundamental to euryhalinity. This study elucidates the distinct adaptive strategies of the brain and gills in the four-finger threadfin (Eleutheronema tetradactylum), an aquaculture species of growing importance, during long-term (30-day) acclimation to low salinity (5 versus 25 control). A profound dichotomy in tissue-specific plasticity was uncovered: while the brain maintained remarkable transcriptional stability with only 10 differentially expressed genes (DEGs), the gills underwent extensive remodeling with 702 DEGs. Gill DEGs were functionally enriched in ion transport and metabolic remodeling, highlighted by the significant upregulation of the Na⁺-Cl⁻ cotransporter (slc12a10) and the prolactin receptor (prlr), coupled with a profound downregulation (log₂FC = −5.97) of aquaporin-1 (aqp1). This indicates a concerted strategy to enhance ion uptake while minimizing water permeability. In contrast, the brain’s subtle response was dominated by the upregulation of key neuroendocrine hormones, including growth hormone (gh), prolactin (prl), and pro-opiomelanocortin (pomc). This suggests a top-down regulatory cascade. Integrative pathway analysis identified the PI3K-Akt and JAK-STAT signaling pathways as the primary conduits linking central hormonal signals to peripheral physiological adjustments. These results demonstrate that the euryhalinity of E. tetradactylum is achieved through a highly efficient strategy: a transcriptionally stable brain provides precise endocrine commands that orchestrate robust peripheral remodeling in the gills. This study deciphers the molecular basis of the brain–gill axis in osmoregulation and provides a rich repository of candidate genes for the genetic improvement of low salinity tolerance in aquaculture.