Osteoarthritis (OA) represents one of the most frequently occurring painful conditions. Pain is the major OA symptom, involving both peripheral and central neurological mechanisms. OA pain is initiated from free axonal endings located in the synovium, periosteum bone, and tendons, but not in the cartilage. The nociceptive message involves not only neuromediators and regulating factors such as neuronal growth factor (NGF) but also central modifications of pain pathways. OA pain is a mixed phenomenon where nociceptive and neuropathic mechanisms are involved in both the local and central levels. OA pain perception is influenced by multiple environmental, psychological, or constitutional factors, and OA pain intensity is not correlated with joint degradation. OA pain may present with different clinical features: constant and intermittent pain, with or without a neuropathic component, and with or without central sensitization. Finally, OA pain should be considered as a complex and not unique pain condition, where precise clinical assessment may drive specific therapeutic approaches.