Objective To study the application of the animal model of chronic fatigue syndrome, and to provide reference for its animal experimental methods and model improvement. Methods Using "chronic fatigue syndrome, animal model" and "chronic fatigue syndrom, animal model" as search terms, we searched in China Knowledge, Wanfang and PubMed databases. Literature on animal models of chronic fatigue syndrome was compiled from July 2000 to July 2023, and experimental animals, modeling methods, positive drugs, and detection indexes were sorted out, and a database was established for statistics and analysis. Results A total of 155 articles were included; the most experimental animals were male SD rats of SPF grade and 6-8 weeks of age, with weights of 180-220g; the most used mice were male KM mice of 18-22g and 6-8 weeks of age; the most used positive drug was ginseng saponin tablets; the most used modeling method was the method of "forced cold water swimming + chronic restraint"; the most used modeling method was the method of "forced cold water swimming + chronic restraint"; the most used modeling method was the method of "forced cold water swimming + chronic restraint". +The most widely used modeling method is the "forced cold water swimming" method, and the modeling cycle is mostly concentrated in 14 days, and most of them adopt the method of intervention while modeling; the testing indexes are mainly behavioral, which mainly include the exhaustion swimming experiment, the open field experiment, the rat-tail suspension experiment, the Morris water maze experiment, and the observation of the general state of the animals, and the second is the serum biochemical indexes, and the most frequently detected indexes are serum MDA, SOD, TNF-alpha, IOD, and IBP, TNF-α, IL-1β, CORT, IL-2, IFN-γ, ACTH, GSH-Px, IgG, IgA, IL-6, etc. The rest of the indicators were selected according to the research purpose, including the indexes of spleen, thymus, etc., the morphological indicators detected by HE staining and ultrastructural electron microscopy, the immunohistochemistry-related indicators, the CRH and Smilax detected by fluorescence PCR, the CRH, the Smilax, the Smilax, and the Smilax. The mRNA expression indexes of CRH, Smad4, BDNF, CREB, IFN-γ, NRF-1, TFAM, Tlr4, etc., and the protein expression indexes of BDNF, CREB, ERK, Bmal1, Clock, NGF, PGC-1α, SIRT1, Smad4, Caspsae-3, etc., were determined by Western blot method. and other related protein expression indicators. Conclusion At present, the pathogenesis of chronic fatigue syndrome is still unclear, and the animal model is mainly based on the stress modeling method of "forced cold water swimming + chronic restraint", which simulates the physical and mental fatigue state of human beings; there is no uniform regulation on the criteria for the formation of animal models, and the evaluation of the model is based on the application of a variety of behavioral experiments individually or in combination, and the objective evaluation indexes are mostly used to argue the etiology of the disease and evaluate the effectiveness of interventions. The objective evaluation indexes are mostly used to prove the conjecture of etiology and evaluate the effectiveness of interventions; the results of the application of various test indexes show that chronic fatigue syndrome may be related to inflammatory response, neurological dysfunction, and mitochondrial dysfunction, and there may be abnormalities in the pathogenesis of immune function, energy metabolism, cell proliferation, and cell death, which is expected to provide reference for the application of the model, and to provide ideas for the model"s refinement. The excavated content is expected to provide reference for the application of the model and provide ideas for the improvement of the model.