Objective: To explore the changes and clinical significance of serum levels of high mobility group box-1 protein (HMGB1), transforming growth factor β1 (TGF-β1), and bone morphogenetic protein-7 (BMP-7) in neonatal respiratory distress syndrome. Methods: Forty-five neonates with respiratory distress syndrome received in Taihe Hospital from January 2017 to February 2018 were selected as an observation group, and 45 healthy newborns in Taihe Hospital were selected as a control group during the same period. We compared the general clinical data, arterial blood gas indexes, index levels of serum HMGB1, TGF-β1, and BMP-7 in the two groups, and analyzed the correlation among serum HMGB1, TGF-β1, and BMP-7 indexes. Results: The Apgar score, gestational age, and birth weight of the observation group were lower than those of the control group, with a statistically significant difference (P<0.05); the arterial partial pressure of oxygen (PaO2) in the observation group was lower than that in the control group, and the arterial partial pressure of carbon dioxide (PaCO2) and oxygen saturation (SaO2) were higher than those in the control group, with a statistically significant difference (P<0.05); HMGB1, TGF-β1, and BMP-7 in the observation group were significantly higher than those in the control group, with a statistically significant difference (P<0.05). Spearman correlation analysis showed that serum HMGB1, TGF-β1, and BMP-7 were all positively correlated (r=0.511, 0.473, 0.615, P<0.05). Conclusion: The expression of serum HMGB1, TGF-β1, and BMP-7 in children with respiratory distress syndrome was significantly increased, which could aggravate the patient’s condition through inflammatory stimulation, oxidative stress, and other ways. Serum HMGB1, TGF-β1, and BMP-7 could be used as clinical evaluation indexes for the improvement of the patient’s condition.