Objective To study the pathogenesis of hyperuricemia combined with nonalcoholic fatty liver disease (HUA-NAFLD) based on the PI3K/ Akt/ NF-κB signaling pathway. Methods Sixty-four SD rats were randomly divided into blank, HUA, NAFLD and HUA-NAFLD groups with 16 rats in each group. Samples were collected at weeks 8 and 12. Serum biochemical indexes were measured. Pathological changes and lipid deposition in liver tissue were observed by hematoxylin-eosin staining and oil red O staining. Relevant proteins in PI3K/ Akt and NF-κB signaling pathways in liver tissues were measured by Western blot. Results Compared with the other three groups, the liver index of rats in the HUANAFLD group was increased significantly (P<0. 05) with a large number of fat vacuoles in hepatocytes, s blurred structure of the hepatic cord, and more severe liver histopathology. Compared with the blank group, UA and LDL levels in the HUA group were increased, HDL levels in the NAFLD group were decreased, UA, TC, TG and LDL levels in the HUA-NAFLD group were increased, and HDL levels were decreased (P<0. 05). Compared with the HUA-NAFLD group, TC, TG, and LDL levels were decreased in the HUA group, and UA, TG, and LDL levels in the NAFLD group were decreased (P<0. 05). Compared with the blank group, AKT and p65 phosphorylation levels in the NAFLD group were increased significantly, AKT, PI3K, p65 and IκκB phosphorylation levels in the HUA-NAFLD group were increased significantly. Compared with the HUA-NAFLD group, AKT and p65 phosphorylation levels in the HUA-NAFLD group were decreased significantly (P<0. 05). The IκκB phosphorylation level was decreased significantly in the HUA group. Compared with the HUA group, the p65 phosphorylation level in the NAFLD group was significantly increased (P< 0. 05). Conclusions Compared with the single disease group, the HUA-NAFLD group had more abnormal biochemical indexes and more severe liver lesions. The PI3K/ Akt/ NF-κB signaling pathway might play a major role in the pathogenesis of HUA, NAFLD and HUA-NAFLD.