Objective: To study the evaluation value of serum pulmonary surfactant protein A (SP-A) and interleukin-6 (IL-6) levels on severity and prognosis of neonatal respiratory distress syndrome (NRDS). Methods: Seventy-five children with NRDS admitted in our hospital from March 2019 to March 2021 were selected as the observation group, and 70 premature infants without NRDS delivered in our hospital in the same period were selected as the control group. The serum SP-A and IL-6 levels between the observation group and the control group, and the observation group children with different degree disease and prognosis were compared, and Logistic regression analysis was used to analyze the relationship between serum SP-A and IL-6 and the prognosis of children with NRDS. Results: The serum SP-A and IL-6 levels in the observation group children were significantly higher than those in the control group (all P<0.05); serum SP-A and IL-6 levels in children with different disease degrees in the observation group was statistically significant (all P<0.05); the serum SP-A and IL-6 levels in dead children of the observation group were significantly higher than those in the survival children, with statistical significance (P<0.05); the logistic regression analysis showed that serum SP-A and IL-6 were risk factors affecting the prognosis of NRDS (P<0.05). Conclusion: Serum SP-A and IL-6 levels are helpful to evaluate the severity and prognosis of patients with NRDS, and have high clinical application value.