Non-steroidal anti-inflammatory drugs (NSAIDs) are widely prescribed, but their long-term use frequently results in gastric mucosal injury. Emerging evidence indicates that, beyond cyclooxygenase inhibition, mitochondrial dysfunction represents a central mechanism driving NSAID-induced gastric epithelial damage. This review aims to critically synthesize current evidence on mitochondria-centered pathways involved in NSAID-induced gastric ulceration and to evaluate the therapeutic relevance of melatonin in this context. We highlight how NSAIDs impair mitochondrial bioenergetics, promote excessive reactive oxygen species generation, disrupt membrane potential, and activate apoptotic signaling, thereby compromising mucosal integrity. Importantly, melatonin exerts multifaceted gastroprotective actions by preserving mitochondrial function, restoring redox homeostasis, modulating apoptosis, and facilitating mucosal repair. Collectively, the available data identify mitochondria as both the primary site of injury and a viable therapeutic target in NSAID-induced gastric ulcers. This mechanistic framework positions melatonin as a promising adjunct strategy for mitigating NSAID-associated gastric damage and improving mucosal defense.