Bacillus subtilis JZXJ-7 isolated from shrimp paste can significantly degrade histamine under salt stress but the mechanism is unclear. This study aims to evaluate the effect of 170 and 340 mmol/L NaCl on B. subtilis JZXJ-7 growth, histamine degradation, antioxidant enzymes (catalase (CAT), superoxide dismutase (SOD) and glutathione S-transferase (GST)) activities and Na+/K+-ATPase activity. Furthermore, comparative metabolomics was used to investigate histamine biodegradation mechanism by B. subtilis JZXJ-7 subjected to salt stress. Both 170 and 340 mmol/L NaCl promoted B. subtilis JZXJ-7 growth in late stages of reproduction (32−48 h), increased histamine degradation rate by 64.85% and 79.87% (P < 0.05), Na+/K+-ATPase activity to 6.28 (P < 0.05) and 11.63 U/mg (P < 0.01) respectively. NaCl treatment significantly increased the activities of CAT, GST and SOD (P < 0.05), amino acids and its metabolites (33.39%), benzene and substituted derivatives (12.05%), heterocyclic compounds (10.62%), organic acids and derivatives (9.75%), aldehydes, ketones, esters (5.59%) and nucleotides and its metabolites (4.58%). Metabolite set enrichment analysis revealed NaCl induced differential metabolic pathways of D-glutamine, D-glutamate, L-arginine, L-proline, histidine and glycerophospholipids, L-lysine degradation, and aminoacyl-tRNA biosynthesis. Exposure to 340 mmol/L NaCl up-regulated carbohydrate, glutathione and glycerophospholipid metabolism. The new insights into the mechanism of salt stress to promote B. subtilis JZJX-7 growth, energy metabolic pathways and to degrade histamine provide the theoretical basis for application of B. subtilis JZXJ-7 in food fermentation industry.