Knee osteoarthritis (KOA) often causes joint pain, weakness and mobility disorders, which seriously affects people's daily life and makes them unable to work and study normally. Traditional Chinese medicine (TCM) prescription Danggui Sini Decoction (DGSND) has been widely used in clinical practice and achieved good results. But there is no high-level evidence to support this result. The aim of this study is to evaluate DGSND's efficacy and safety in the management of KOA.We will search 7 electronic databases including Chinese National Knowledge Infrastructure (CNKI), Wanfang Data (WF), Chinese Scientific Journals Database (VIP), Chinese databases SinoMed (CBM), PubMed, Embase, and Cochrane Library databases. All the publications, with no time restrictions, will be searched without any restriction of language and status, the time from the establishment of the database to September 2022. Two reviewers will independently assess the quality of the selected studies, NoteExpress and Excel software will be used to extract data, and the content will be stored in an electronic chart. Different researchers will separately screen the titles and abstracts of records acquired potential eligibility which comes from the electronic databases. Full-text screening and data extraction will be conducted afterward independently. Statistical analysis will be conducted using RevMan 5.4 software.This study will compare the effects of DGSND and any other different methods on patients with KOA to provide high-quality, evidence-based clinical recommendations.The study provides a trustable clinical foundation for DGSND in the treatment of KOA.Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.