Objective The purpose of this study was to evaluate the efficacy and safety of intranasal dexmedetomidine compared with traditional medications for rescue sedation during radiological scanning in infants under 12 months with congenital heart disease. Methods On an intention to treat protocol, of this prospective single-blinded randomized clinical trial, a total 347 infants diagnosed with congenital heart diseases who were not adequately sedated after initial oral dose of 50 mg/kg chloral hydrate were randomly divided into three groups. Group A received intramuscular Phenobarbital of 5mg/kg. Group B received second oral dose chloral hydrate 25 mg/kg. Group C received intranasal dexmedetomidine 1g/kg. Sedation onset and duration, heart rate, and oxygen saturation, parent satisfaction were recorded. Results The success rate of rescue sedation among three groups was 75.8%, 83.3% and 90.7% . There were significant differences in success rate in Group C compared with Group A. The sedation induced time, wake-up time and the total sedation time in group C were 8.0(5.0,13.0)min, 66.0(50.0,92.8)min, 96.0(80.0,122.8)min respectively. There were no significant differences among three groups in wake-up time and the total sedation time; However, the sedation induced time was significantly shorter in Group C as compared to that in Group A. The proportion of infants with right to lefte shunt subgroup successfully sedated was more than that of the other two subgroups. The incidence of side-effects were 3.2%, 7.6% and 4% separately with no significantly differences (P ≥ 0.05). There were no significant differences in hemodynamic changes among three groups. Conclusions A dosage of intranasal dexmedetomidine 1g/kg was found to be effective in infants under 12 months with congenital heart disease during radiological scanning as a rescue sedative with quicker sedation onset time and longer sedation time and appears to be more effective in infants with right to left shunt lesions. It did not increase the incidence of side effects and hemodynamic changes.