The aim of the current study is to evaluate the use of an enteral clonidine transition for the prevention or management of dexmedetomidine withdrawal symptoms in critically ill children not exposed to other continuous infusion sedative agents. A retrospective, single-center study was conducted in patients ≤ 18 years of age admitted to the pediatric intensive care unit who received a continuous infusion of dexmedetomidine for ≥ 24 hours and who were prescribed enteral clonidine within 72 hours of dexmedetomidine discontinuation. Predefined withdrawal terminology was established to assess for hypertension, tachycardia, agitation, tremors, and decreased sleep. A total of 105 patients were included and received enteral clonidine for prevention or management of dexmedetomidine withdrawal symptoms, with 13 patients (12.4%) requiring a taper modification to manage withdrawal symptoms. The median duration of dexmedetomidine infusion was 120.5 hours (95.5, 143.5) and median peak infusion rate was 1 µg/kg/h (1, 1.2). A higher cumulative dexmedetomidine dose of 119.2 µg/kg (96.6, 154.9) and duration of 142.9 hours (122.6, 158.3) were noted in patients who required a taper modification. Risk factors for dexmedetomidine withdrawal such as dexmedetomidine duration and cumulative dose may help predict patients at the highest risk of withdrawal that would benefit from an enteral clonidine taper to prevent dexmedetomidine withdrawal symptoms. An enteral clonidine taper can be effective in the prevention and management of dexmedetomidine withdrawal symptoms.