Osteoarthritis (OA) is a degenerative disease that affects multiple cells and associated extracellular matrix (ECM). Chondrocytes and chondroextracellular matrix together constitute articular cartilage tissue. Any factors that affect the activity of chondrocytes and destroy the metabolic balance of the chondrocyte ECM will lead to the inability of articular cartilage to perform normal functions. The articular subchondral bone and articular cartilage must be coordinated to resist enough friction and mechanical stress, so the articular subchondral bone lesion will aggravate the articular cartilage defect and vice versa. Synoviocytes, including fibroblast-like synoviocytes (FLSs) and synovial macrophages at the joint, are also important factors that cause low-grade chronic progressive inflammation of OA. Regulation of phenotype transformation of synovial macrophages has become another possible target for the clinical treatment of OA. Ubiquitination and deubiquitination are the main post-translational protein modification pathways in the human body, which are widely involved in multiple signaling pathways and physiological processes. Naturally, they also play a very important regulatory role in the occurrence and development of OA. These effects are summarized in this review, including (A) regulating the aging and apoptosis of chondrocytes, FLSs and osteoblasts; (B) regulation of ECM degradation; (C) regulation of macrophage phenotypic transformation; (D) modulation of skeletal muscle and adipose tissues. Ubiquitination targeting drugs for OA treatment are also listed. Depending on the high efficiency of ubiquitination and deubiquitination, understanding OA-related ubiquitination pathways can help design more efficient drugs to treat OA and provide more potential targets for clinical treatment. The Translational Potential of This Article. In this paper, the ubiquitination-related pathways in osteoarthritis (OA), including aging, apoptosis and autophagy in chondrocytes, osteoblasts, FLSs and macrophages were investigated. In particular, several ubiquitination-related targets are expected to be effective approaches for OA clinical treatment. In addition, in the process of OA occurrence and development, the complex relationship between the local joint area and other tissues including skeletal muscle and adipose tissue is also discussed. These myokines and adipokines from musculoskeletal tissues are all expected to become efficient targets for OA treatment apart from the joint itself. In addition, those myokines secreted by cardiovascular tissues would show potential therapeutic effects as well. What if altering the contents for these ubiquitination-related targets in the serum through exercise will provide a new idea for OA therapy or prevent OA from deteriorating continuously?