Objective With reference to the method of operationalization of concept in the field of sociology, this study developed a methodological framework for intervention trials of Chinese medicine (CM) under the mode of syndrome dominating disease. Methods First, an operational definition of the syndrome dominating disease research model was clarified to provide the scope and direction of the methodological framework construction. Then a scoping review was conducted to identify the design features of clinical researches under the model to summarize the basic structure and content of the framework; furthermore, in-depth interviews were carried out to collect the views and suggestions of CM experts on this type of study, which added details to the framework. Finally, a survey was conducted to evaluate the rationality and feasibility of the methodological framework. Results A total of 74 studies were included and 12 CM experts were interviewed, and the results of the literature and interview study were synthesized to form a preliminary methodological framework. Thirty-two experts participated in the survey and most of them held a positive assessment of the rationality of the framework, then according to the experts’ suggestions, the final methodological framework which was a four-level structure with 25 items was established. Conclusion Following the internationally recognized methods and steps, this study develops a rational and feasible methodological framework for CM trials under the mode of syndrome dominating disease, which can provide references for future studies’ design, implementation and evaluation.