Abstract: Objective: The study aimed to explore the mechanism of Athelia rolfsii polysaccharides (AEPS) protected against liver of lead-exposed mice. Methods: Mice were randomly assigned into normal control group (NC), model control group (MC), positive control group (PC), AEPS low dose group (LD), AEPS middle dose group (MD), AEPS high dose group (HD), ATRA alone group (ATRA+NC), ATRA intervention group (ATRA+MC), ATRA+AEPS high dose group (ATRA+HD). Lead levels, antioxidant indexes and functional indexes in the liver of lead-exposed mice were determined, the pathological changes were also evaluated by hematoxylin-eosin (HE) staining. The activity of glutathione-s-transferase (GST) and the levels of glutathione (GSH) were also measured. The protein levels of apoptosis-associated proteins and multidrug resistance-associated protein 2 (MRP2) in liver tissues were determined, as well as nuclear factor erythroid-2-related factor 2 (Nrf2) in liver cell nucleus. Results: Low, middle and high dose of AEPS enhanced the lead ion excretion ability of MRP2 participation, decreased lead accumulation in mice liver significantly in a dose dependent manner (P<0.05). AEPS enhanced antioxidant activity of mice liver (P<0.05), restored liver function (P<0.05), alleviated liver pathological injury induced by lead in a dose dependent manner, as well as suppressed hepatocyte apoptosis of lead-exposed mice significantly (P<0.05). AEPS also promoted Nrf2 nuclear translocation in the liver (P<0.05). However, ATRA reduced the protective efficacy of AEPS on the liver of lead-exposed mice. Conclusion: AEPS reduced lead accumulation in the liver in a Nrf2-dependent manner, and showed liver protective effect.