Rationale <p>The orexin (OX) system plays a crucial role in regulating cognitive functions. Dysregulation of this system has been implicated in several dementia-related neurological disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD) and dementia with Lewy bodies (DLB).</p> Objectives <p>This review aims to synthesize current research on the involvement of the OX system in dementia-related neurological diseases, focusing on its effects on cognitive function and its potential as a therapeutic target.</p> Results <p>The OX system, encompassing hypothalamic neuropeptides and receptors (OX1R and OX2R), exhibits dysregulation in neurodegenerative diseases associated with dementia. Changes in OX concentrations strongly correlate with cognitive decline, and this correlation varies with disease progression. OX regulates essential molecular mechanisms, including neuronal survival, synaptic plasticity, neural network integrity, and circadian rhythm stability—processes impaired as cognitive deficits intensify. These findings emphasize OX’s critical and context-dependent role in cellular resilience and cognitive function.</p> Conclusions <p>OX system emerges as a multifaceted therapeutic target for dementia-related cognitive impairment. Its effects vary across disease stages, initially offering neuroprotection but later contributing to pathology. Moreover, OX’s involvement in circadian rhythm regulation complicates its clinical utility, as disruptions exacerbate cognitive deficits. These opposing functions highlight the need for tailored, stage-specific interventions to maximize cognitive benefits while minimizing adverse signaling.</p>