Objective To investigate the effect of exosomes derived from human adipose-derived mesenchymal stem cells preconditioned with Jiangzhi Yigan Decoction (JZYGT-Exo) on ferroptosis in a metabolic associated fatty liver disease (MAFLD) cell model and its underlying mechanism. Methods Human adipose-derived mesenchymal stem cells were treated with serum containing JZYGT to obtain JZYGT-Exo, which were characterized using transmission electron microscopy (TEM) and nanoparticle tracking analysis. An in vitro MAFLD model was established by inducing HepG2 cells with a mixture of oleic acid (OA) and palmitic acid (PA). The experiments were divided into the following groups: Model group, JZYGT-Exo group, JZYGT-Exo + Erastin group, and JZYGT-Exo + Fer-1 group. Lipid metabolism was assessed by Oil Red O staining, and measurements of intracellular triglyceride (TG) and glucose levels. The mode of cell death was screened using the CCK-8 assay. Levels of superoxide dismutase (SOD), malondialdehyde (MDA), reactive oxygen species (ROS), catalase (CAT), and glutathione peroxidase (GSH-Px) were detected. Mitochondrial membrane potential and morphology were evaluated using JC-1 and Mito-Tracker probes, respectively. Mitochondrial ultrastructure was observed by TEM, and the protein expressions of GPX4 and Nrf2 were detected by Western blot. Results JZYGT-Exo were successfully isolated and identified, and were effectively taken up by MAFLD model cells. JZYGT-Exo intervention significantly reduced intracellular lipid deposition, as well as TG and glucose levels. The cell death mode screening indicated that JZYGT-Exo specifically antagonized Erastin-induced ferroptosis. Regarding ferroptosis-related indicators, JZYGT-Exo increased the activities of SOD, CAT, and GSH-Px, decreased the levels of MDA and ROS, enhanced mitochondrial membrane potential, improved mitochondrial morphology and ultrastructure, reduced mitochondrial iron deposition, and up-regulated the protein expression of GPX4 and Nrf2. These effects were partially reversed by Erastin and further synergistically enhanced by Fer-1. Conclusion Exosomes from adipose-derived mesenchymal stem cells preconditioned with Jiangzhi Yigan Decoction can ameliorate lipid metabolism disorders and inhibit ferroptosis in MAFLD model cells by regulating key proteins of oxidative stress and ferroptosis. The mechanism of action may be related to the activation of the Nrf2/GPX4 signaling pathway.