This article explored the protective effects of zinc supplementation on diabetic liver injury and studied the underlying mechanisms that zinc supplementation reduced ER stress and autophagy in diabetic liver. Type 2 diabetes mellitus-like Wistar rat models were intragastrically administrated with ZnSO4 15 mg/kg daily for 53 days. Liver changes were examined by biochemical assay of serum, histopathological assay, immunohistochemical assay, radioimmunoassay and Western blotting. In results, compared with diabetes model control, zinc supplementation reduced the lipid peroxidation MDA levels, and enhanced the anti-oxidation T-AOC levels (P<0.05). H&E staining showed that pathological changes in diabetic liver were improved by zinc supplementation. Zinc supplementation enhanced MT protein expression in diabetic liver. In immunohistochemical assay, the amount of p-Akt positive cells was apparently increased, and the amount of LC3-II positive cells were lowered. Western blots of autophagy-associated LC3-II protein and endoplasmic reticulum(ER) stress-associated GRP78 proteins were lowered following a long-term zinc supplementation. In conclusion, zinc supplementation enhanced MT protein synthesis and Akt/PKB phosphorylation, which relieve GRP78-linked ER stress and LC3-II-linked autophagy. Zinc supplementation improved liver conditions in T2DM rat models through multiple pathways, in which GRP78-linked ER stress and LC3-II-linked autophagy are ameliorated to some degree. This finding is conducive to understanding the mechanisms that zinc supplementation prevent diabetic liver injury.