Objectives: The aim of this study was to evaluate the effect of high-flow nasal cannula (HFNC) after early extubation on children undergoing cardiac surgery. Methods: This randomized controlled clinical trial was performed among 92 children aged 1 to 24 months undergoing cardiac surgery from March 5 to August 30, 2020, in a pediatric post-cardiac surgery intensive care unit (ICU). The patients were randomized to receive either HFNC or conventional oxygen therapy after extubation. Arterial blood samples were collected after anesthesia induction, after the end of the surgery, at the time of entering the ICU while they were intubated, 6 hours after entering the ICU, before removing the endotracheal tube, immediately after extubation, as well as 1, 6, 12, 24, and 36 hours after extubation. The patients were compared regarding PaCO2, PaO2/FiO2 ratios, respiratory failure, need for reintubation, development of atelectasis, pneumothorax, pleural effusion, and length of ICU stay. Results: The patients were similar regarding demographic characteristics, the duration of surgery, and mechanical ventilation (P > 0.05). On the first and second days after the surgery, the mean modified radiologic atelectasis score (m-RAS) was lower in the HFNC group compared to the conventional oxygen therapy group (P < 0.05). The frequency of respiratory failure did not differ in the groups before and after the surgery (P > 0.05). PaCO2 was lower in the HFNC group than in the control group after extubation (P < 0.001). PaO2/FIO2 ratio was significantly higher in the HFNC group one hour after extubation and afterward in comparison to the control group (P < 0.001). The need for re-intubation (P < 0.013) and the length of ICU stay (P < 0.001) were significantly lower in the HFNC group compared to the control group. Conclusions: It was found that HFNC could improve the respiratory parameters and reduce postoperative pulmonary complications in infants following a congenital heart surgery.