Neonatal respiratory distress syndrome (NRDS) is a common respiratory disorder occurring in premature infants, and some microRNAs (miRNAs) have been demonstrated to play critical roles in NRDS progression. This study aimed to measure relative expression of miR-375 in infants with NRDS, and further evaluate the clinical significance of miR-375 in predicting the onset and clinical prognosis of NRDS in infants. This study collected umbilical cord blood from 180 premature neonates, including 90 neonates with NRDS and 90 non-NRDS neonates. Quantitative real-time PCR was used to detect relative expression level of miR-375. The diagnostic value of miR-375 in screening NRDS neonates from control neonates and its predictive accuracy for clinical prognosis were evaluated by receiver operating characteristic analysis. The relationship of miR-475 with disease onset and clinical outcomes in NRDS infants was assessed by univariate and multivariate logistic regression analyses. Relative miR-375 expression was upregulated in NRDS neonates, and high levels of miR-375 were observed in NRDS grade III-IV cases compared to those early-stage neonates. miR-375 had relatively high diagnostic accuracy to screen NRDS neonates and was independently associated with NRDS onset in infants. Moreover, relative miR-375 expression was upregulated in NRDS neonates with poor prognosis and could independently predict the clinical outcomes of NRDS neonates with considerable predictive accuracy. Umbilical cord serum miR-375 is elevated and associated with NRDS onset and clinical outcomes in NRDS neonates. Thus, miR-375 may serve as a biomarker for the diagnosis and prognosis of infants with NRDS.