Aim: Propofol-remifentanil-dexmedetomidine-based total intravenous anesthesia is widely used, but ensuring the safety of the sleep-wakefulness transition and hemodynamic stability remains a challenge. This study aimed to investigate the influence of orexinergic neuron gene polymorphisms on interindividual variability in the time to loss of consciousness (LOC), time to wake, and cardiovascular fluctuations. Methods: A total of 250 patients were included in the study. Gene polymorphisms were detected using the Agena Bioscience MassARRAY system. Anesthesia induction began with propofol and maintained with propofol and remifentanil. Dexmedetomidine was administered before anesthesia induction. The time to LOC, time to wake, heart rate (HR), and mean arterial pressure (MAP) were documented. Results: HCRTR2 rs2292040 and rs76380807 were significantly associated with the time to LOC, and HCRTR2 rs7774031 was correlated with the time to wake. HCRTR2 rs3122162, rs3122169, and rs74296544 were correlated with HR fluctuations, and HCRTR1 rs2176807, rs2271933, rs871634, and HCRTR2 rs74296544 were associated with MAP fluctuations. Multiple linear regression analysis revealed that a TCI concentration of propofol > 4 μg ml-1 at the time of LOC and dexmedetomidine were influencing factors for the time to LOC, whereas HCRTR2 rs7774031 influenced the time to wake. Baseline HR, baseline MAP, dexmedetomidine, HCRTR2 rs3122162, and HCRTR1 rs2176807 were predictive factors for cardiovascular susceptibility. The predictive models for the time to LOC, time to wake, HR, and MAP fluctuations accounted for 41.89%, 3.36%, 35.56%, and 47.41% of variations, respectively. Conclusion: Genetic variants of orexinergic neurons may affect sleep-wakefulness transition and hemodynamic stability during propofol, dexmedetomidine, and remifentanil anesthesia.