Osteoarthritis (OA) is one of the leading causes of chronic pain and dysfunction. It is essential to comprehend the nature of pain and cartilage degeneration and its influencing factors on OA treatment. Voltage-gated ion channels (VGICs) are essential in chondrocytes and extracellular matrix (ECM) metabolism and regulate the pain neurotransmitters between the cartilage and the central nervous system. This narrative review focused primarily on the effects of VGICs regulating pain neurotransmitters and chondrocytes metabolism, and most studies have focused on voltage-sensitive calcium channels (VSCCs), voltage-gated sodium channels (VGSCs), acid-sensing ion channels (ASICs), voltage-gated potassium channels (VGKCs), voltage-gated chloride channels (VGCCs). Various ion channels coordinate to maintain the intracellular environment’s homeostasis and jointly regulate metabolic and pain under normal circumstances. In the OA model, the ion channel transport of chondrocytes is abnormal, and calcium influx is increased, which leads to increased neuronal excitability. The changes in ion channels are strongly associated with the OA disease process and individual OA risk factors. Future studies should explore how VGICs affect the metabolism of chondrocytes and their surrounding tissues, which will help clinicians and pharmacists to develop more effective targeted drugs to alleviate the progression of OA disease.