Objective To study animal models of chronic fatigue syndrome and to provide a reference for improvements in related animal experimental method and models. Methods Using “ chronic fatigue syndrome, animal model” and “chronic fatigue syndrome, animal model” as search terms, we searched in the China Knowledge, Wanfang,and PubMed databases from July 2000 to July 2023. We compiled the literature on animal models of chronic fatigue syndrome and analyzed the experimental method and models. Content relating to experimental animals, modeling method,positive drugs, and detection indexes was sorted, and a database was set up for statistics and analysis. Results A total of 155 articles were included from the validated literature; most of the experimental animals were male SD rats of specificpathogen free grade and body weights of around 180~ 220 g. Most of the mice used were KM males of 18~ 22 g. The most commonly used positive drug was ginsenoside tablets; and the typical modeling method was “forced cold water swimming + chronic restraint”. Testing indexes were mainly behavioral and included exhaustive swimming test, open field test, rat tail suspension test, Morris water maze test, and animal’ behavioral cycle, and observations of the general state of the animals. Modeling cycles mostly spanned 14 days. The most frequently tested indexes were serum MDA, SOD, TNF-α, IL-1β,CORT, IL-2, IFN-γ, ACTH, GSH-Px, IgG, IgA, and IL-6. The remaining indicators were selected according to the research purpose and included spleen, thymus, and other organ indexes; morphological indicators detected by hematoxylin and eosin pathological staining; ultrastructural electron microscopy indicators; immunohistochemistry-related indicators,and related mRNA and protein expression indicators detected by fluorescence quantitative PCR and Western blot method. mRNA and protein expression indexes were determined via a variety of tests, but the frequency of their application was low. At present, animal models are mainly used to study the effects of interventions and the etiology and mechanisms of the disease. Conclusions The pathogenesis of chronic fatigue syndrome is still unclear, and animal models are mainly based on stress modeling with “forced cold water swimming + chronic restraint”, which simulates the physical and mental fatigue states of humans. No standard criteria for the formation of animal models are available, and the evaluation of models is based on the application of a variety of behavioral experiments, individually or in combination. Objective evaluation indexes are mostly used to validate the etiology of the disease and evaluate the effectiveness of interventions. The result of various test indexes have shown that chronic fatigue syndrome may be related to inflammatory responses, neurological dysfunction, and mitochondrial dysfunction, and there may be abnormalities in immune function, energy metabolism, cell proliferation, and cell death. This summary is expected to provide a reference for researchers planning to employ these models and ideas for model refinements.