Background: Osteoarthritis is the most common degenerative joint disease. It is associated with significant socioeconomic burden and poor quality of life, mainly due to knee osteoarthritis (KOA), and related total knee arthroplasty (TKA). Since early detection method and disease-modifying drug is lacking, the key of KOA treatment is shifting to disease prevention and progression slowing. The prognostic prediction models are called for to guide clinical decision-making. The aim of our review is to identify and characterize reported multivariable prognostic models for KOA about three clinical concerns: (1) the risk of developing KOA in the general population, (2) the risk of receiving TKA in KOA patients, and (3) the outcome of TKA in KOA patients who plan to receive TKA. Methods: The electronic datasets (PubMed, Embase, the Cochrane Library, Web of Science, Scopus, SportDiscus, and CINAHL) and gray literature sources (OpenGrey, British Library Inside, ProQuest Dissertations & Theses Global, and BIOSIS preview) will be searched from their inception onwards. Title and abstract screening and full-text review will be accomplished by two independent reviewers. The multivariable prognostic models that concern on (1) the risk of developing KOA in the general population, (2) the risk of receiving TKA in KOA patients, and (3) the outcome of TKA in KOA patients who plan to receive TKA will be included. Data extraction instrument and critical appraisal instrument will be developed before formal assessment and will be modified during a training phase in advance. Study reporting transparency, methodological quality, and risk of bias will be assessed according to the TRIPOD statement, CHARMS checklist, and PROBAST tool, respectively. Prognostic prediction models will be summarized qualitatively. Quantitative metrics on the predictive performance of these models will be synthesized with meta-analyses if appropriate. Discussion: Our systematic review will collate evidence from prognostic prediction models that can be used through the whole process of KOA. The review may identify models which are capable of allowing personalized preventative and therapeutic interventions to be precisely targeted at those individuals who are at the highest risk. To accomplish the prediction models to cross the translational gaps between an exploratory research method and a valued addition to precision medicine workflows, research recommendations relating to model development, validation, or impact assessment will be made.