Osteoarthritis (OA) is a common chronic degenerative disease of joints, which is one of the main causes of chronic pain and disability. Several studies have shown that OA is causally associated with many factors, such as cytokines, metabolic diseases, nutrients, gut microbiota, and life behaviors. The risk factors included obesity, hyperlipidemia and bone mineral density, and the protective factors included the use of potassium-sparing diuretics and aldosterone antagonists, folic acid and arginine. These factors influence the progression of OA mainly by participating in the body's inflammatory response and material metabolic processes or by altering the biomechanics of weight-bearing joints. In addition, the chronic pain symptoms of OA, the expression of inflammatory factors, and the use of non-steroidal anti-inflammatory drugs may increase the risk of other diseases, such as type 2 diabetes, severe depression, and Parkinson's disease. Mendelian randomization is a new method to explore the causal association between diseases and risk factors. This method uses the random allocation of genetic variants to simulate randomized controlled trials and uses the instrumental variables related to risk factors and diseases to test the causal association between them. This review included the Mendelian randomization-related studies of OA and analyzed the causal association between OA and metabolic diseases, cardiovascular diseases, musculoskeletal diseases, central nervous system diseases, psychiatric diseases, cytokines, metabolomics, nutrients, gut microbiota, life behavior, telomere length and mitochondrial heterogeneity, which is of great significance for the prevention and treatment of OA.