Objective To observe the effects of autophagy inhibition on microglia activation state and secretion of tumor necrosis factor-α (TNF-α) in rats with epilepsy, and to investigate its impacts on neurons and epilepsy.Methods Thirty Wistar rats were randomly divided into control group (n=6) and epilepsy group (n=24). In the epilepsy group, the rat model of epilepsy was made by pentylenetetrazol. After successful model establishment, 18 rats in the epilepsy group were randomly and equally divided into epileptic control group, 3-methyladenine (3-MA) group, and rapamycin (RAPA) group. Changes in behavior and electroencephalogram were observed and recorded in each group. HE and Nissl staining were used to determine neuronal injuries in the CA1 region. Immunofluorescence staining and Western blot were used to measure the expression of microtubule-associated protein light chain 3 (LC3), cluster of differentiation 68 (CD68), and TNF-α in the hippocampus.Results The epileptic control group showed that epilepsy caused neuronal injuries. The epileptic control group had significantly higher expression of LC3, CD68, and TNF-α than the control group (all P<0.05). Compared with the epileptic control group, the 3-MA group had milder epilepsy, a reduced number of injured neurons, and significantly lower expression of LC3, CD68, and TNF-α (all P<0.05). There were no significant differences in the severity of seizure or the expression of CD68 and TNF-α between the RAPA group and the epileptic control group (all P>0.05); however, the number of injured neurons and expression of LC3 were significantly increased in the RAPA group than in the epileptic control group (all P<0.05).Conclusions Autophagy occurs during epilepsy. It activates the microglia, promotes the secretion of TNF-α, and causes neuronal injuries. Autophagy inhibition can regulate the microglia, reduce the secretion of TNF-α, protect the neurons, and finally reduce the severity of epilepsy.