<p>Salinity is a limiting factor for many marine organisms. Shifts in ambient salinity can cause osmotic conditions and trigger the immune response in fish. In this study, we investigated the effects of different salinity conditions on the liver of euryhaline yellowfin seabream <i>Acanthopagrus latus</i> by combining histological, physiological, and transcriptomic analyses after the exposure of the fish to salinities of 0, 4, 9, and 34 (coded 0S, 4S, 9S, 34S hereafter) for four weeks. In the 0S and 34S groups, increased vacuolization, looser cell arrangement, and vague cell boundaries were observed, whereas no pathological damage was detected in the 4S and 9S groups. The activities of antioxidant enzymes were significantly reduced in the 0S and 34S groups compared to the 9S group, while no significant difference was observed between the 4S and 9S groups. Regarding gene expression patterns, both 0S and 34S groups significantly inhibited the expression of ion transporter genes and altered genes involved in both innate and adaptive immunity. Consistent with the inhibition of antioxidant defenses, antioxidant genes were inhibited by 0S and 34S conditions, including solute carrier family (<i>slc2a2, slc22a6</i>, and <i>slc47a1</i>) in the 0S group, as well as glutathione peroxidase 8 (<i>gpx8</i>) in the 34S group. In addition, differentially expressed genes (DEGs) related to the extracellular region and cell junctions, such as collagen-related (<i>colla1, ecm1</i>, and <i>lox</i>) and claudin-related genes (<i>cladn5b</i>), were down-regulated in the 34S group. Notably, in the 4S group, the DEGs related to energy metabolism promoted the tricarboxylic acid cycle and fatty acid metabolism upregulated, thereby supporting the energetic demands for growth, development, and physiological homeostasis. This study provides critical insights into the molecular mechanisms underlying the responses of the liver to different salinity conditions in euryhaline fish.</p>