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Perioperative neurocognitive disorders (PND) remain a major clinical and public health challenge despite substantial scientific progress over the past two decades. Unidentified traits continue to limit the development of effective pharmacologic strategies and evidence-based care practices, particularly for high-risk patients. Emerging insights into the genetic and epigenetic architecture of PND are revealing novel mechanistic targets and paving the way toward precision approaches to perioperative brain health. Expanding biobanks and genome-wide association studies are accelerating the ability to explore genetic and epigenetic determinants of PND. Genetic factors influence key pathways associated with PND, particularly those involved in neurodegeneration, circadian rhythm dysregulation, and inflammation. Epigenetic mechanisms, including DNA methylation, histone modifications, and noncoding RNA activity, further link genetic susceptibility with environmental exposures and perioperative stressors, modulating immune activation and neurotransmission in ways that may predispose to PND. Unlike static genetic variants, epigenetic alterations are dynamic and potentially reversible, offering unique opportunities for biomarker discovery and therapeutic intervention. Insights from genetic and epigenetic discoveries can be aggregated into risk scores and integrated with other multi-omics approaches. In this narrative review, we summarise evidence linking genetic and epigenetic traits to PND and outline future directions for applying multi-omics approaches in the perioperative setting. Collectively, these advances are establishing the foundation for a precision medicine framework aimed at enhancing prediction, prevention, and management strategies to improve brain health.