Objectives <p>To compare the clinical outcomes and hospitalization costs of Minimally Invasive Surfactant Therapy (MIST) vs. Intubate–Surfactant–Extubate (INSURE) in preterm infants with RDS.</p> Methods <p>In this retrospective comparative study, 113 preterm infants with RDS treated with MIST (<i>n</i> = 54) or INSURE (<i>n</i> = 59) between 2018 and 2024 were included. Clinical data and pre-/post-intervention respiratory parameters (PaO₂, FiO₂, PaO₂/FiO₂ ratio, SpO₂) were analyzed. Group comparisons utilized chi-square, independent samples, and paired t-tests. Logistic regression identified predictors of bronchopulmonary dysplasia (BPD), and multiple linear regression explored factors affecting total hospitalization cost.</p> Results <p>Post-intervention oxygenation improved significantly in both groups (<i>p</i> &lt;0.001). No statistically significant difference in adjusted total hospitalization cost was observed between the MIST and INSURE groups. In the multivariable linear regression analysis, gestational age and PaO₂ were independently associated with total hospitalization cost, whereas the treatment group was not a significant predictor (<i>p</i> = 0.900).The treatment group (MIST vs. INSURE) showed a lower odds of BPD; however, this association did not reach statistical significance after adjustment (OR = 0.420, <i>p</i> = 0.102).</p> Conclusions <p>MIST was associated with superior short-term clinical outcomes and lower healthcare costs compared with INSURE for neonatal RDS management. These findings support MIST as a safe, effective, and cost-efficient approach. Further randomized controlled trials are required to confirm these benefits and evaluate long-term outcomes before universal adoption in clinical practice.</p>