High density and intensive aquaculture of fish often lead to some nutritional and metabolic related diseases. This experiment was designed to investigate the effect of Pomelo Polysaccharide on reducing fat deposition. Five groups of feeds were prepared: control group, low-fat diet group (7.57% fat content), low-fat diet with pomelo polysaccharide group (TDF1 group), high-fat diet group (15.48% fat content), and high-fat diet with pomelo polysaccharide group (TDF2 group). Orange-spotted groupers after 8 weeks of rearing, samples were taken to analyze the growth performance, nutrient composition, liver morphology, enzyme activities and the expression of immune-related genes in liver tissues. The results showed that the weight gain rate (WGR) of groupers in the low-fat diet group was significantly lower than the control group (P < 0.05), while the TDF1 group and TDF2 group were higher than those in the low-fat diet group and high-fat diet group, respectively. Liver damage occurred in the low-fat diet group and the high-fat diet group, while the TDF1 group and the TDF2 group showed improvement in liver tissue structure damage, and the liver lipid droplets in the TDF 2 group decreased significantly compared with the high-fat diet group. Moreover, the TDF2 group significantly inhibited the up-regulation of inflammation and apoptosis-related genes IL-1β, IL-8, caspase-3, and caspase-8. These results indicate that the addition of pomelo polysaccharide can reduce the fat deposition in the liver caused by feeding high-fat feeds, and can have a certain effect on the enhancement of immune function and improve the health of liver of groupers.