Osteoarthritis (OA), a prevalent age-related disease, is increasingly recognized as a multifactorial condition. This comprehensive review provides a multifaceted perspective on the organ-joint crosstalk contributing to OA, transcending the traditional focus on local joint pathology. Based on current research, we discussed the brain-joint, gut-joint, muscle-joint interactions in the etiology and progression of OA. In brain-joint axis, the neuroendocrine regulation, circadian rhythms, and leptin signaling influence joint tissues. We also discussed the role of prostaglandin E2 in skeletal interoception and its potential as a therapeutic target. The gut-joint axis is underscored by the impact of gut microbiota dysbiosis on systemic inflammation and metabolic disorders, both of which are implicated in OA pathogenesis. Furthermore, age-related sarcopenia, characterized by muscle mass and strength loss, is identified as a significant risk factor. Sarcopenia may contribute to OA progression through compromised mechanical support, systemic inflammation, and muscle-derived myokines. Finally, we synthesize the evidence supporting the modulation of circadian rhythm, skeletal interoception, gut microbiome, and muscle mass as innovative strategies for OA management. The organ-joint crosstalk is integral to the complex pathogenesis of OA, highlighting the multifactorial nature of OA and the potential for targeted therapeutic interventions. By integrating these multidimensional perspectives, we aim to enhance our understanding of OA pathogenesis and explore potential pharmacological targets.