The present study was conducted to investigate the regulatory mechanism of liver injury in largemouth bass Micropterus salmoides (LMB) fed low protein high starch diets. Two isolipidic and isoenergetic diets were formulated with different protein and starch ratios, being named as diets P49S9 (48.8 % protein and 9.06 % starch) and P42S18 (42.4 % protein and 18.2 % starch). Each diet was fed to triplicate replicates of LMB (initial body weight, 4.65 ± 0.01 g) juveniles. Fish were fed to visual satiation for 8 weeks. The results indicated that though the P42S18 fish up-regulated the feeding ratio to meet their protein requirements, feeding efficiency ratio and growth performance were impaired in treatment P42S18 as compared to treatment P49S9. Periodic acid-Schiff (PAS) staining showed glycogen accumulated in the liver of LMB fed low protein high starch diets, and the reason should be attributed to down-regulated expression of the glycogenolytic glycogen debranching enzyme. Lower liver lipid level was associated with feeding low protein high starch diets in LMB, which should be resulted from the changes in hepatic glycerolipid metabolism regulated by lipoprotein lipase (representative of triglyceride synthesis, up-regulated) and diacylglycerol acyltransferase (representative of triglyceride breakdown, down-regulated). Though fasting plasma glucose level was comparable, treatment P42S18 performed inferior glucose tolerance to treatment P49S9. Hematoxylin-eosin (HE) and TdT-mediated dUTP Nick-End Labeling (TUNEL) staining suggested that feeding low protein high starch diets induced disruption of structural integrity, inflammation and apoptosis in the hepatocytes of LMB. As expected, KEGG pathways analysis indicated that many of the up-regulated differentially expressed genes were enriched in AGE (advanced glycation end product)/RAGE (receptor for AGE), Toll-like receptor and apoptosis signaling pathways. Our transcriptome data revealed that feeding low protein high starch diets might promote the accumulation of AGEs in LMB, which bound to RAGE and subsequently induced PI3K/Akt signal pathway. The activation of Akt induced NF-κB translocation into the nucleus thus releasing proinflammatory factors including tumor necrosis factor-α (TNF-α) and interleukin-8. The release of these inflammatory factors concomitantly induced T cell stimulation and natural killer cells chemotactic effects through Toll-like receptor signaling pathway. Besides mediating inflammation and immune response, TNF-α signal transduction participated in mediating apoptosis through the receptor of TNF (TNF-R1) pathway by up-regulating the expression of caspase 8 and cytochrome c. In conclusion, our results demonstrated that feeding low protein and high starch diets induced hepatocytes inflammation and apoptosis in LMB through the PI3K/Akt/NF-κB signaling pathway.