Introduction and objective: This study aimed to compare the efficacy of high-flow nasal cannula (HFNC) and non-invasive ventilation (NIV) interventions in children who presented with respiratory distress at the RSUP Dr. Mohammad Hoesin Palembang. Materials and methods: An open-label randomised controlled clinical trial was conducted in the paediatric intensive care unit of Dr. Moh. Hoesin Hospital, Palembang, from October 2021 to June 2022, in children aged one month to 18 years with respiratory distress. This study cohort consisted of two groups. The first (n = 42) and second (n = 43) groups received HFNC and NIV, respectively. Comfort was assessed using the COMFORT B scale. Results: A total of 85 children with respiratory distress were enrolled. Only one child (2.5%) had treatment failure in the NIV group, with no failures in the HFNC group. Most children in both groups showed significant improvements in their heart and respiratory rates, oxygen saturation, and blood gas parameters (p < 0.001). The COMFORT B scale scores in the HFNC group were significantly better than those in the NIV group (NIV: 13 vs. HFNC: 3; p = 0.006). The duration of respiratory support in both groups was 1–2 days, with a length of stay of ≥4 days in the paediatric intensive care unit. Conclusions: NIV and HFNC are equally effective as initial therapies for mild-to-moderate respiratory distress in children. HFNC is more comfortable than NIV, well tolerated, and easy to use, with a high success rate as initial therapy for patients with respiratory distress.