Abstract: Objective To investigate the protective effect of L. reuteri DSM17938 strain against oxidative stress in a neonatal mouse model of necrotizing enterocolitis (NEC) and explore the possible mechanism. Methods Ninety-six 10-day-old neonatal C57BL/6J mice were equally randomized into control group, NEC group, and NEC+ L. reuteri group. The pathological changes of the ileocecal intestinal tissue were evaluated with HE staining and double-blind pathological scoring. The mRNA and protein expressions of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in the intestinal tissues were detected using quantitative real-time PCR and ELISA, respectively. Colorimetric assays were used to determine the activity of superoxide dismutase (SOD) and its inhibition rate, malondialdehyde (MDA), glutathione (GSH), oxidized glutathione (GSSG), and GSSG/ GSH ratio. Results Compared with those in the control group, the neonatal mice in NEC group showed significant weight loss (P<0.05), obvious intestinal injury, increased pathological scores (P<0.05), increased expressions of TNF-α and IL-1β mRNA and proteins (P<0.05), decreased SOD activity and inhibition rate, decreased GSH, and significantly increased MDA, GSSG, and GSSG/GSH ratios (P<0.05). Treatment with L. reuteri obviously decreased the pathological scores, expressions of TNF-α and IL-1β (P<0.05), MDA, GSSG, and GSSG/GSH ratio (P<0.05), and significantly increased SOD activity, its inhibition rate, and GSH level in the mice with NEC, but the survival rate was not significantly different between NEC and L. reuteri-treated groups (P>0.05). Conclusion L. reuteri DSM17938 can offer protection against NEC in mice by reducing oxidative stress and increasing antioxidant capacity of the intestinal tissue to suppress intestinal inflammations.