<p>Orofacial pain encompasses a diverse group of disorders that pose a significant clinical challenge, often progressing from acute to chronic conditions due to a disconnect between clinical diagnosis and underlying pathophysiology. This review provides a synthesis of the mechanisms driving this transition and evaluates emerging therapeutic strategies that target them. First, we dissect the pathophysiological mechanisms of acute pain, including peripheral sensitization and transient central sensitization; and then detail how these processes can become maladaptive, leading to chronic pain states sustained by a combination of persistent nociceptive input, neuropathic alterations, and nociplastic changes involving dysfunctional descending modulation and central network reorganization. Building on this mechanistic framework, we critically appraise novel therapeutic approaches, including targeted pharmacotherapies such as selective ion channel and endocannabinoid system modulators, alongside non-pharmacotherapeutic interventions that encompass neuromodulation techniques designed to regulate central neural plasticity and psychologically grounded therapies. By integrating molecular evidence with clinical presentations, this review offers a framework for advancing towards a more precise, mechanism-based management of orofacial pain.</p> Graphical abstract <p></p>