Objective To refine the rules and essence of the speculative method of pathogenesis cognition by analyzing the reaction after treatment in "Treatise on Febrile Diseases". Methods Through an objective and comprehensive analysis of the original text of "Treatise on Febrile Diseases" reflecting the concept of therapeutic response pathogenesis, the theory of therapeutic response pathogenesis in "Treatise on Febrile Diseases" was accurately refined and explained in detail. Results The pathogenesis of therapeutic response in "Treatise on Febrile Diseases" includes: pathogenesis analysis based on pharmacodynamic response after drug treatment, pathogenesis analysis based on pharmacodynamic response of drug trial, and pathogenesis analysis based on therapeutic response after mistreatment (including sweating, vomiting, purgation, fire therapy or acupuncture). Conclusion The detailed interpretation of the theory of therapeutic response pathogenesis in "Treatise on Febrile Diseases" has important enlightening significance and guiding value for the research and application of the pathogenesis theory of "Treatise on Febrile Diseases" and the syndrome differentiation theory of traditional Chinese medicine, as well as the improvement of clinical efficacy, which is worthy of further study.