This study aimed to investigate whether using lung ultrasound (LUS) scores in premature newborns with respiratory distress syndrome (RDS) allows for earlier surfactant therapy (within the first 3 h of life) than using FiO2 criteria. This was a randomised, non-blinded clinical trial conducted in a neonatal intensive care unit. The inclusion criteria were newborns with a gestational age of ≤ 32 weeks and RDS. Patients meeting the inclusion criteria were randomly assigned to two groups: the ultrasound group, administered surfactant based on LUS score and/or FiO2 threshold, and the control group, guided by FiO2 only. Fifty-six patients were included. The ultrasound group received surfactant earlier (1 h of life vs. 6 h, p < 0.001), with lower FiO2 (25% vs. 30%, p = 0.016) and lower CO2 (48 vs. 54, p = 0.011). After surfactant treatment, newborns in the ultrasound group presented a greater SpO2 (p = 0.001) and SpO2/FiO2 ratio (p = 0.012).Conclusions: LUS score allowed an earlier surfactant therapy, reduced oxygen exposure early in life and a better oxygenation after the treatment. This early surfactant replacement may lead to reduced oxygen exposure. What is Known: • Lung ultrasound scores predict the need for surfactant therapy in premature newborns. What is New: • This study shows that using lung ultrasound scores improves the timeliness of surfactant replacement compared with using FiO2 alone.