Objective To investigate the effect of fluoxetine on autophagy in the hippocampal dentate gyrus in rats with epilepsy accompanied by depression.Methods A total of 60 Sprague-Dawley rats were randomly divided into control group, model group, fluoxetine group, and 3-methyladenine (3-MA) groups. Body weight, food intake, and open-field test were used to assess the level of depression; immunohistochemistry was used to mesaure the protein expression of beclin1, LC3-I, and mammalian target of rapamycin (mTOR) in the hippocampal dentate gyrus, and quantitative real-time PCR was used to measure the mRNA expression of beclin1, LC3-I, and mTOR.Results After drug intervention, the model group had significantly lower body weight, food intake, and numbers of vertical and horizontal movements than the control group(P<0.01), and the fluoxetine group and the 3-MA group had significantly higher values of the above indices than the model group (P<0.01 or P<0.05). Compared with the control group, the model group had significant increases in the expression of beclin1 and LC3-I and a significant reduction in the expression of mTOR (P<0.01), and compared with the model group, the fluoxetine group and the 3-MA group had significant reductions in the expression of beclin1 and LC3-I and a significant increase in the expression of mTOR (P<0.01).Conclusions Fluoxetine may inhibit autophagy by improving the expression of beclin1, LC3-I, and mTOR in the hippocampal dentate gyrus of rats with epilepsy accompanied by depression.