The effects of diets containing the probiotic Leuconostoc mesenteroides B4 and its products, isomaltooligosaccharide and dextran, on the viable bacterial counts in the intestine, short chain fatty acids in feces, immune status, and pathogen resistance of spotted grouper (Epinephelus coioides) were investigated in the present study. 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, and the Vibrio spp. counts of the intestines of the groupers that were fed with all the experimental diets were significantly lower than that of the control group, while the levels of total short chain fatty acids in the feces of the fish fed with the experimental diets for 4 and 8 weeks were significantly increased compared to that of the control group fish. Before and after Vibrio harveyi challenge, the antiprotease and lysozyme activity levels of the fish fed with the experimental diets were also significantly higher than those of the control group fish (p < 0.05); the respiratory bursts of the fish fed with the L. mesenteroides B4＋isomaltooligosaccharide and L. mesenteroides B4＋dextran diets were significantly higher than those of the control group (p< 0.05). The highest survival rates were observed in the fish fed with the L. mesenteroides B4＋isomaltooligosaccharide and L. mesenteroides B4＋dextran diets for 8 weeks and then challenged with V. harveyi, with the survival rates of those groups being significantly increased compared to that of the control group (p < 0.05). Overall, the results of this study indicate that the dietary administration of L. mesenteroides B4 and its products, isomaltooligosaccharide and dextran, could be of benefit in terms of enhancing the resistance to pathogens of orange-spotted grouper.