Abstract Background Transthoracic echocardiography can be performed under sedation in children with Down syndrome who have neurological or behavioral problems. This study aimed to compare the efficacy and safety of intranasal dexmedetomidine and oral chloral hydrate in children with Down syndrome who are undergoing transthoracic echocardiography. Methods This retrospective cohort study reviewed the electronic medical records of patients with Down syndrome who underwent transthoracic echocardiography under oral chloral hydrate or intranasal dexmedetomidine sedation between June 2014 and September 2021. The patients were divided into oral chloral hydrate and intranasal dexmedetomidine groups according to the main agents used for sedation. The primary endpoint was the outcome of single-dose sedative agents, and the groups were compared using a propensity score weighting analysis. Results In total, 149 patients (chloral hydrate group, n = 75; dexmedetomidine group, n = 74) were included in the final analysis. After propensity score weighting, 150 and 148 patients were included in the chloral hydrate and dexmedetomidine groups, respectively. The success rate of the initial sedative medication was significantly higher in the dexmedetomidine group than in the chloral hydrate group (89.1% vs. 80.7%, p = 0.0412) after adjustment for propensity score weighting. The success rate of the final sedative medication was higher in the dexmedetomidine group than in the chloral hydrate group (before propensity score weighting, 98.7% vs. 86.7%; after propensity score weighting, 98.5% vs. 86.8%; both p values