Objective To investigate the role of dynamin-related protein 1 (Drp-1) and peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) in the lung tissues of neonatal rats with meconium aspiration syndrome (MAS) and its mechanism. Methods Fifty 2-3-week-old SD neonatal rats were randomly divided into five groups (n=10): control group, model group and SN50 low, medium and high concentration groups. In control group, 2 ml/kg of saline was injected into the trachea after tracheal exposure, and 2 ml/kg of meconium suspension was injected into the trachea of the rest of groups; after 24 h, control and model groups were left untreated, and 100 μl of each of SN50 concentrations of 10, 30, and 60 μg/ml was injected into SN50 low, medium, and high concentration groups intraperitoneally; the rats of each group were killed after 6 h, and the chest X-rays, the gross views of the lungs, the lung wet/dry weight ratios (W/D), and the lungs of the rats in control group and model group were examined. After 6 h, the rats in each group were executed, and the pathological changes of lung tissue were observed by chest radiographs, lung gross view, lung wet/dry weight ratio (W/D) and HE staining; Western blotting was used to detect the changes of nuclear factor κB (NF‑κB) (p65), p-NF‑κB p65 (p-p65), Drp-1, and PGC-1α proteins expression in neonatal rat lung tissues, and immuno-histochemistry was used to observe the expression of p65, Drp-1, and PGC-1α related proteins expression in neonatal rat lung tissues. Results Compared with control group, model group showed inflammatory infiltration in the chest radiograph and gross view, and the W/D and lung injury pathology scores were significantly higher (P<0.05); compared with model group, the chest radiograph and gross view of inflammation were slightly reduced in SN50 low, medium and high concentration groups, and the W/D and lung injury pathology scores were significantly lower (P<0.05).Western blotting showed that, compared with control group, the protein expression levels of p-p65 and Drp-1 in the lung tissues of neonatal rats were significantly higher in model group (P<0.05), and the protein expression level of PGC-1α was significantly lower (P<0.05); compared with model group, the protein expression levels of p-p65 and Drp-1 were significantly lower in SN50 low, medium, and high concentration groups (P<0.05), and the difference in the protein expression level of PGC-1α in SN50 low concentration group was not statistically significant (P>0.05), whereas the PGC-1α expression levels in SN50 medium and high concentration groups were significantly higher (P<0.05); the difference in the total p65 protein expression levels in each group was not statistically significant (P>0.05). Immunohistochemical assay results showed that, compared with control group, p65 and Drp-1 protein expression levels were significantly higher in model group (P<0.05), and PGC-1α protein expression level was significantly lower (P<0.05); compared with model group, p65 protein expression level was significantly lower in SN50 low concentration group (P<0.05), and the difference in Drp-1 and PGC-1α protein expression levels were not statistically significant (P>0.05), Drp-1 protein expression level was significantly lower (P<0.05), and PGC-1α protein expression level was significantly higher (P<0.05) in SN50 middle and high concentration groups. Conclusion Fecal inhalation can induce lung tissue inflammation in neonatal rats, and the mechanism may be related to enhanced oxidative stress, promotion of mitochondrial dysfunction, activation of the Drp-1/NF-κB signaling pathway, and inhibition of PGC-1α protein expression.