The effect of the probiotic,Leuconostoc mesenteroides B4, and its products, isomaltooligosaccharide and dextran, on growth performance, short chain fatty acid of feces, viable bacterial count of intestine, digestive enzymes, immune status, and pathogen resistance of spotted grouper Epinephelus coioides were investigated. Spotted grouper were fed (1) control, (2) isomaltooligosaccharide, (3)L. mesenteroides B4, (4)L. mesenteroides B4 + isomaltooligosaccharide, and (5)L. mesenteroides B4 + dextran supplemented diets for up to 8 weeks. Final weight of spotted grouper fed with (3)L. mesenteroides B4, (4)L. mesenteroides B4 + isomaltooligosaccharide, and (5)L. mesenteroides B4 + dextran in the diets were significantly higher than the control group ( p < 0.05). The alkaline, neutral, and acid protease activities of digestive tract in fish fed diet with (3)L. mesenteroides B4, (4) L. mesenteroides B4+isomaltooligosaccharide , and (5)L. mesenteroides B4 + dextran were significantly increased than the control group ( p < 0.05). The amylase activities of digestive tract in fish fed diet with experimential feed groups were significantly increased than the control group ( p < 0.05). The lipase activities of digestive tract in fish fed diet with (2) isomaltooligosaccharide and (4) L. mesenteroides B4 + isomaltooligosaccharide were significantly increased than the control group ( p < 0.05). The levels of total short chain fatty acid of feces in fish fed with experimental feeds for 4 and 8 weeks were significantly increased. All the experimental diets significantly decreased Vibrio spp. count of the intestines of groupers. Antiprotease and lysozyme activity before and after challenged with Vibrio harveyi of spotted grouper fed with the experimental diets were significantly increased than the control group ( p< 0.05). The respiratory burst after challenged with V. harveyi of fish fed with (4)L. mesenteroides B4 + isomaltooligosaccharide, and (5)L. mesenteroides B4 + dextran were significantly higher than the control ( p < 0.05). The higher survival rates after challenged with V. harveyi were observed in fish fed diet with (4)L. mesenteroides B4 + isomaltooligosaccharide, and (5)L. mesenteroides B4 + dextran significantly increased from the control group ( p < 0.05). Overall, the results of this study indicate that dietary L. mesenteroides B4, and its products, isomaltooligosaccharide and dextran could be an effective method for enhancing the growth performance and disease resistance in orange-spotted grouper.