Objective To investigate the effect of lidocaine on the high mobility group box 1 (HMGB1)/Toll‑like receptors 4 (TLR4)/nuclear factor‑κB (NF‑κB) pathway in the hippocampus of rats with sepsis‑associated encephalopathy (SAE). Methods A total of 100 male SD rats were anesthetized by intraperitoneal injection of esketamine (50 mg/kg). After anesthesia, all the rats were inserted with electroencephalogram electrodes. Then, 10 rats were selected as sham operation group (Sham group) by random number table method, and the remaining 90 rats were used to establish a sepsis models through the cecal ligation and puncture (CLP) method. After the sepsis model was established, SAE rats were screened by electroencephalogram. 10 SAE rats were selected as SAE group by random number table method, while another 10 SAE rats were selected as a SAE+lidocaine group (SAE+LD group). Furthermore, 10 rats were selected among those without SAE as a sepsis group (CLP group) by random number table method, totaling four groups. The SAE+LD group was sacrificed after continuous pumping of lidocaine at 10 mg·kg−1·h−1 for 6 h, and the sham group, the CLP group and the SAE group were given isotonic saline solution. After implementation of all intervention measures, their neurological behaviors were evaluated. Then, the rats were sacrificed and their levels of tumor necrosis factor‑α (TNF‑α), interleukin (IL)‑6, NF‑κB and HMGB1 in the hippocampus were detected by enzyme-linked immunosorbent assay (ELISA), and the HMGB1 mRNA levels in the hippocampus were detected by real‑time fluorescence quantitative polymerase chain reaction (PCR). Results Compared with the Sham group, the CLP group, the SAE group and the SAE+LD group showed increased mRNA levels of TNF‑α, IL‑6, NF‑κB, HMGB1 and HMGB1 in hippocampus tissues (P<0.05) and decreased neurological behavior scores (P<0.05). Compared with the CLP group, the SAE group presented increased mRNA　levels of TNF‑α, IL‑6, NF‑κB, HMGB1 and HMGB1 in hippocampus tissues (P<0.05), while reduced neurological behavior scores were observed in the SAE group and the SAE+LD group (P<0.05). Compared with the SAE group, the SAE+LD group showed decreased mRNA levels of TNF‑α, IL‑6, NF‑κB, HMGB1 and HMGB1 (P<0.05) and increased neurological behavior scores (P<0.05). There was no statistical difference in other indexes (P>0.05). Conclusions Continuous infusion of lidocaine can effectively inhibit the expression of HMGB1 in the hippocampus of rats with SAE, reduce the inflammatory response of SAE rats by inhibiting the HMGB1/TLR4/NF‑κB pathway, and improve the neurological behavior score of SAE rats.