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Background Necrotizing enterocolitis (NEC) is a severe gastrointestinal disease predominantly affecting preterm infants. The exact pathogenesis remains unclear, although prematurity, ischemia/hypoxia, formula feeding, suboptimal feeding practices, infection, and aberrant gut microbiota colonization are recognized as primary high-risk factors. Due to the unclear pathogenesis, insidious onset in some infants, and lack of highly effective preventative strategies, novel interventions are sought. Studies suggest that Limosilactobacillus reuteri can ameliorate colitis by modulating the intestinal barrier, microbial composition, and inflammatory responses. Bacterial outer membrane vesicles (OMVs) contribute to maintaining gut microbial diversity and homeostasis, offering the advantage of retaining beneficial and immunogenic properties of parent bacteria while circumventing risks associated with live bacteria. Therefore, we aimed to investigate the prophylactic or mitigating effects of OMVs derived from L. reuteri strain HI-120 on NEC.Methods In vitro, HI-120 OMVs were applied to prevent inflammation in an LPS-induced intestinal epithelial cell model. In vivo, HI-120 OMVs were prophylactically administered in an LPS-induced NEC model established in (SD) rat pups; macro- and micro-scopic observations were performed. Intestinal inflammation, assessed via histopathological analysis, and the expression levels of key inflammatory mediators (IL-6, IL-1β, NF-κB) in intestinal tissues were detected after intervention using ELISA kits and Western blot analysis.Results The prophylactic use of HI-120 OMVs in the rat pup NEC model demonstrated significantly reduced intestinal damage and hemorrhagic foci compared to the NEC model group. Pathological scoring based on histopathological analysis revealed notable improvement in the HI-120 OMV group. Both the HI-120 OMV treatment group and the NEC model group exhibited weight loss starting from day 3. By day 5, the mean weight of pups in the OMV intervention group was higher than that in the NEC model group. Pup mortality commenced on day 5, with the HI-120 OMV group exhibiting lower mortality than the NEC model group. In vitro experiments demonstrated that pre-treatment with HI-120 OMVs significantly attenuated the expression of inflammatory cytokines IL-6, IL-1β, and NF-κB compared to the LPS-induced inflammation model group.Conclusions These findings collectively indicate that OMVs derived from HI-120 exert protective effects against NEC development. HI-120 OMVs represent a promising therapeutic strategy for mitigating NEC.