Osteoarthritis (OA) is a chronic degenerative disease characterized predominantly by cartilage degradation, wherein extracellular matrix (ECM) proteins play pivotal roles in its pathogenesis. Proteins such as Asporin (ASPN), Cartilage Intermediate Layer Protein (CILP), Chondroadherin (CHAD), Fibulin-3 (EFEMP1), Pannexin 3 (PANX3), and C-terminal cross-linking telopeptide of type II collagen (CTX-II) exhibit aberrant expression patterns in OA cartilage, influencing chondrocyte metabolism, signaling pathways, and matrix homeostasis. This review provides a comprehensive overview of the altered expression and molecular functions of these ECM-related proteins in OA, emphasizing their interactions with key signaling cascades including TGF-β, Wnt, and BMP pathways. Incorporating recent advances from single-cell sequencing and gene editing technologies, we explore how these proteins serve as potential biomarkers and therapeutic targets. Furthermore, the review delves into the impact of post-translational modifications of ECM proteins on OA pathology, aiming to elucidate mechanisms that underpin precise diagnosis and targeted treatment strategies. By synthesizing current findings, this article seeks to advance understanding of ECM protein-mediated regulatory networks in OA and foster the development of innovative interventions for cartilage preservation and repair.