To elucidate ZHANG Zhongjing′s thought of treatment based on disease differentiation rooted in qi suitability, this paper primarily draws on the discussions in Inner Canon of Yellow Emperor, Treatise on Cold Pathogenic Diseases, and Synopsis of Golden Chamber to analyze the close relationship between qi suitability, pathogenesis, and treatment method. Early Chinese medicine pioneers, represented by ZHANG Zhongjing, integrated philosophical concepts into medicine at the inception of their academic systems, thereby developing a coherent framework from qi suitability to pathogenesis and further to treatment method. Qi suitability refers to regular qi changes, including the opening and closing of qi movement and the waxing and waning of qi establishment. Once the opening, closing, increase, and decrease of the bodily qi deviate from the normal range, it leads to stagnation, excess, leakage, and decline in pathogenesis, manifesting as various symptoms. To guide the transformation of pathogenesis, the therapeutic method in traditional Chinese medicine applies the properties of medicinal substances. For example, the pungent divergent, sour astringent, bitter stimulating, and sweet soothing effects of medicinal flavors constitute a sequential balance relationship of qi suitability. Guided by the principle of orthodox treatment for mild or slow conditions and retrograde treatment for severe or urgent conditions, these flavors either restore patency or balance, thereby helping the body return to a state of natural harmony of yin-yang. Thus, ZHANG Zhongjing′s thought on disease differentiation and treatment is both simple and profound, serving as the scientific core of the classical formula treatment system and retaining significant academic value for the development of contemporary Chinese medicine.