Type 2 diabetes mellitus plagues many people in China and the world, and its nephritis complication is the leading cause of death for patients. Paecilomyces hepiali contained various functional components, especially polysaccharides, which possesses well pharmacological activities. In this study, polysaccharide purified from Paecilomyces hepiali fermented mycelium entitled PHEA was obtained, and its structure was systemically characterized using fourier transform infrared spectroscopy (FT-IR) and nuclear magnetic resonance (NMR). In C57BL/KsJ (BKS).Cg-Dock7 m +/+ Lepr db /JNju mice (db/db mice), via detecting the alternations on biochemical criterions, pathological indicators and protein expressions related to nuclear factor-E2-related factor 2 (Nrf2) and nuclear factor-κB (NF-κB) signaling in serum and/or tissues including muscle, liver and kidney after 8-week PHEA administration, the hypoglycemic, hypolipidemic, and anti-diabetic nephropathic activities of PHEA were confirmed. The purified P. Hepiali polysaccharide with the anti-diabetic and -nephritic properties was first reported in this study via regulating Nrf2-meadited NF-κB signaling in db/db mice., (Copyright © 2019 Elsevier Ltd. All rights reserved.)