Objective To investigate the effect of emodin on the expression of the Toll-like receptor 4 (TLR4)-myeloid differentiation factor 88 (MyD88)-nuclear factor kappa-B (NF-κB) inflammatory signaling pathway after status epilepticus (SE) in mice, as well as the mechanism of action of emodin in protecting hippocampal neurons in mice with epilepsy induced by kainic acid. Methods A total of 54 male ICR mice were randomly divided into control group, SE group, and emodin group (200 mg/kg), with 18 mice in each group. A mouse model of SE was established by intraperitoneal injection of kainic acid. The behavioral changes of mice after epileptic seizure were observed; Nissl staining was used to observe the necrosis of hippocampal neurons; RT-PCR and Western blotting were used to measure the mRNA and protein expression of TLR4, MyD88, and NF-κB. Results Emodin intervention significantly reduced the severity and number of seizures, alleviated the necrosis of hippocampal neurons (P<0.05), and downregulated the mRNA and protein expression of TLR4, MyD88, and NF-κB in the hippocampus (P<0.05). Conclusions The TLR4-MyD88-NF-κB inflammatory signaling pathway is activated after SE in mice, and the mRNA and protein expression of the TLR4-MyD88-NF-κB inflammatory signaling pathway is downregulated after emodin intervention. Emodin can exert a protective effect on hippocampal neurons in mice with epilepsy induced by kainic acid, possibly by inhibiting the expression of the TLR4-MyD88-NF-κB inflammatory signaling pathway.