Introduction Midazolam is commonly used as a traditional sedative for the postoperative care of patients with head and neck cancer undergoing free flap reconstruction. To improve the quality of postoperative management, this study aimed to investigate whether the use of dexmedetomidine (DEX) in such patients reduces the risks of agitation, delirium, and postoperative complications compared with traditional sedatives. Materials and Methods Patients who underwent wide excision of head and neck cancer followed by immediate microvascular free flap reconstruction between July 2021 and December 2023 were enrolled. All patients received either midazolam or DEX for sedation in the intensive care unit (ICU). Data collected included patient demographics, cancer-related history, perioperative characteristics, and postoperative outcomes, such as duration of mechanical ventilation, incidence of agitation and delirium, pulmonary infections, ICU length of stay, and complications related to free flap reconstruction. Results A total of 265 patients were included and divided into a traditional sedative group (n = 204) and a DEX group (n = 61). The DEX group demonstrated a significantly lower incidence of postoperative delirium. In addition, both the duration of sedative use and the length of ICU stay were reduced in the DEX group. Multivariate analysis revealed that DEX use was significantly associated with reduced agitation (odds ratio, 2.25; 95% confidence interval, 1.17–4.36; P = 0.016) and shorter mechanical ventilation time. No significant differences were observed between the 2 groups in terms of pulmonary infections or free flap complications. Conclusions The use of DEX following head and neck cancer resection with immediate microvascular free flap reconstruction may enhance the quality of postoperative care in the ICU by reducing delirium, agitation, and length of ICU stay without increasing surgical complications.