INTRODUCTION: Mechanical loading enhances the progression of osteoarthritis. However, its molecular mechanisms have not been established. OBJECTIVE: The aim of this review was to summarize the probable mechanisms of mechanical load-induced osteoarthritis. METHODS: A comprehensive search strategy was used to search PubMed and EMBASE databases (from the 15th of January 2015 to the 20th of October 2020). Search terms included "osteoarthritis", "mechanical load", and "mechanism". RESULTS: Abnormal mechanical loading activates the interleukin-1β, tumour necrosis factor-α, nuclear factor kappa-B, Wnt, transforming growth factor-β, microRNAs pathways, and the oxidative stress pathway. These pathways induce the pathological progression of osteoarthritis. Mechanical stress signal receptors such as integrin, ion channel receptors, hydrogen peroxide-inducible clone-5, Gremlin-1, and transient receptor potential channel 4 are present in the articular cartilages. CONCLUSION: This review highlights the molecular mechanisms of mechanical loading in inducing chondrocyte apoptosis and extracellular matrix degradation. These mechanisms provide potential targets for osteoarthritis prevention and treatment.