Objective To investigate the mechanism of action of the nuclear factor erythroid 2-related factor 2 (Nrf2) / solute carrier family 7 member 11 (SLC7A11) / glutathione peroxidase 4 (GPX4) signaling pathway in nonalcoholic fatty liver disease (NAFLD), and to explore the mechanism of Gegen QinLian Decoction for the treatment of NAFLD, using in vivo and in vitro experiments. Methods Rats were fed with high-fat chow for 24 weeks to induce NAFLD, and were then divided randomly into normal ( C), model ( M), high-, medium-, and low-dose Gegen QinLian Decoction(GGQLT-H, GGQLT-M, GGQLT-L), and metformin (Met) groups. From week 25 onwards, the rats were administered the corresponding drugs by gavage for 2 weeks according to the grouping, until sampling.Levels of the oxidative stress markers malondialdehyde ( MDA) and glutathione (GSH) in the liver tissues were measured in each group using biochemical kits and ferrous iron (Fe²⁺) in rat liver tissues was detected using a Fe²⁺ kit. Nrf2, heme oxygenase-1 ( HO-1), SLC7A11, glutathione synthetase ( GSS), GPX4, and acyl coenzyme A synthetase 4 (ACSL4) mRNA levels in rat liver tissues were measured by reverse transcription quantitative polymerase chain reaction. For cellular experiments lipid accumulation was induced in HepG2 hepatocellular carcinoma cells using 1 mmol / L free fatty acid, to mimic the NAFLD in vitro model. Different concentrations of Gegen QinLian Decoction and metformin-containing serum were added for treatment. Lipid accumulation was detected in the cells in each group by Oil red O staining. The MDA and GSH contents of HepG2 cells in the different groups were determined using appropriate kits, and the ferrous contents were detected using a cell-specific ferrous kit. Expression levels of Nrf2, HO-1, SLC7A11, GSS, GPX4, and ACSL4 mRNA was detected in each group of cells using reverse transcription quantitative polymerase chain reaction. Results In the animal experiments, MDA and Fe²⁺ liver levels were significantly higher in the M group than in the C group, while GSH levels were significantly lower (P<0. 01).GGQLT-H, GGQLT-M and Met groups showed significantly reduced MDA and Fe²⁺ and elevated GSH levels compared with the M group (P<0. 01, P<0. 05). High- and medium-dose Gegen QinLian Decoction and metformin increased Nrf2, HO-1, GSS, and GPX4 mRNA and decreased ACSL4 mRNA expression levels ( P<0. 01, P<0. 05). In cellular experiments, lipid droplets were significantly increased in the HepG2 cell M group compared with those in the C group, and lipid droplets were significantly reduced by Gegen QinLian Decoction and metformin. MDA and Fe²⁺ levels were significantly increased and GSH levels were significantly decreased in the HepG2 M group compared with the levels in the C group ( P<0. 01), while all doses of Gegen QinLian Decoction and metformin significantly decreased MDA and Fe²⁺ levels (P<0. 01) and increased the GSH content (P<0. 01, P<0. 05). Nrf2, GSS, GPX4,and SLC7A11 mRNA expression levels in the GGQLT-H group, Nrf2, HO-1, and SLC7A11 in the GGQLT-L group,HO-1, SLC7A11, and GSS in the GGQLT-M group, and GSS, Nrf2, and HO-1 in the Met group were all significantly increased compared with the findings in the M group (P<0. 01, P<0. 05). ACSL4 mRNA expression levels were significantly decreased in the GGQLT-M and GGQLT-L groups and the Met group (P<0. 01, P<0. 05). Conclusions Gegen QinLian Decoction can improve NAFLD by inhibiting ferroptosis, and its mechanism may be related to regulation of the Nrf2 / SLC7A11 / GPX4 signaling pathway.