The beneficial effects of gut flora on reducing nerve cell apoptosis and inflammation and improving epilepsy (EP) symptoms have been reported, but the specific mechanism of action is still unclear. A series of in vitro and in vivo experiments revealed the relationship between gut microbiota metabolites and the cGAS/STING axis and their role in EP. These results suggest that antibiotic-induced dysbiosis of gut microbiota exacerbated epileptic symptoms, probiotic supplements reduced epileptic symptoms in mice. Antibiotics and probiotics altered the diversity and composition of gut microbiota. The changes in gut bacteria composition, such as in the abundance of Firmicutes, Bacteroidetes, Lactobacillus and Ruminococcus, were associated with the production of short-chain fatty acids (SCFA) in the gut. The concentrations of propionate, butyrate and isovalerate were changed after feeding antibiotics and probiotics, and the increase in butyrate levels reduced the expression of cGAS/STING in nerve cell further reduced Bax protein expression. The reduction of Bax protein attenuated the hippocampal neuron cell apoptosis in PTZ-induced EP and EP progression. Our findings provide new insights into the roles and mechanisms of action of the gut microbiota in attenuating EP symptoms and progression.