Glucose-regulated protein 78 kDa (Grp78) alleviates endoplasmic reticulum stress induced by external stimuli and enhances cell viability. We studied the molecular response mechanisms of Gymnocypris przewalskii to salinity stress. In this study, Grp78 was cloned from G. przewalskii and the response patterns of Grp78 and related genes were analyzed after 5‰, 10‰, and 15‰ salinity stress using qPCR. The results showed that the open reading frame length of Grp78 was 1962 bp, encoding 653 amino acids and containing the conserved domain of the HSP70 superfamily. Grp78 was expressed in nine tissues of G. przewalskii, and its expression in the intestinal tract, liver, and heart was significantly higher than that in the other tissues (n=3, P ＜ 0.05). In gills, with the increase in salinity and the extension of stress time, compared with the blank control group, the expressions of Grp78, Hyou1, Prdx1, Nqo1, and UBC were first inhibited and then gradually upregulated, while the expression of DNAJC2, Cu/Zn-SOD, Mn-SOD, and Hmox1 was first upregulated and then gradually downregulated and then upregulated again. In the kidney and liver, the expression of DNAJC2, Cu/Zn-SOD, Mn-SOD, Hmox1, and Nqo1 showed similar patterns of upregulation, downregulation, and upregulation, respectively. These results indicated that Grp78 and its related genes have complex responses to salinity stress and may be involved in adaptation and coping with salinity stress in G. przewalskii. In addition, Grp78 and its related genes—Hyou1, DNAJC2, Hmox1, Nqo1, UBC, Prdx1, Cu/Zn-SOD, and Mn-SOD—participate in the regulation of antioxidant stress in the body and play important roles in reducing salinity damage.