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Objective To explore the effect of sodium butyrate on brain injury in mice with necrotizing enterocolitis (NEC). Methods A total of 137 3-day-old C57BL/6 mice were randomly divided into Control group (CON group, n=40, without maternal separation), NEC+PBS group (NP group, n=57) and NEC+butyrate group (NB group, n=40). The mice from the NP and NB groups were separated maternally and given either PBS or sodium butyrate by gavage from postnatal day 3 for 7 consecutive days, then a NEC model was established by formula feeding combined with hypoxia and hypothermia for 3 consecutive days. Survival rate, histopathological injury of the intestine, mRNA expression of TNF-α and IL-6 in the brain, and number of activated microglia and astrocytes were observed and detected. Morris water maze and transmission electron microscopy were employed to observe the long-term cognitive impairment and microstructure of myelin, respectively, for the adult mice (4 weeks old). Western blotting was used to measure the protein level of HMGB1 in the intestine and TLR4 as well as NF-κB in the brain. Results Compared with the CON group, the mice of the NP group showed increased mRNA expression of TNF-α(1.51± 0.20 vs 0.67±0.14) and IL-6 (2.03±0.39 vs 1.01±0.17) in the brain (both P < 0.05), raised number of activated microglia (751.00±82.35 vs 284.70±52.01, P < 0.05) and astrocytes (P < 0.05) in the hippocampus, and elevated protein levels of HMGB1 (1.76±0.19 vs 0.73±0.06) in the intestine as well as TLR4 (1.14±0.16 vs 0.81±0.01) and NF-κB (1.21±0.19 vs 0.60±0.15) in the brain (all P < 0.05). In addition, the adult mice in the NP group demonstrated the prolonged escape latency and decreased crossing-platform times, and increased G-ratio (all P < 0.05). After the administration of sodium butyrate, the mRNA expression levels of TNF-α(0.81±0.12 vs 1.51±0.20) and IL-6 (0.93±0.38 vs 2.03±0.39) in the brain were decreased, the activation of microglia was inhibited (468.00±99.59 vs 751.00±82.35), and the number of astrocytes was reduced (all P < 0.05). The decreased expression levels of HMGB1 (1.22±0.11 vs 1.76±0.19) in the intestine and TLR4 (0.88±0.06 vs 1.14±0.16) and NF-κB (0.70±0.19 vs 1.21±0.19) in the brain were also marked in the NB group (all P < 0.05). The adult mice of the NB group showed shortened escape latency, and increased crossing-platform times and myelin thickness (all P < 0.05). Conclusion Sodium butyrate alleviates the neuroinflammation by inhibiting the activation of TLR4-NF-κB signal pathway in the NEC brain, and thus exerts protective effect against NEC-associated brain injury.