Summary The mammalian intestine is colonized with a diverse community of bacteria that perform many beneficial functions but can threaten host health upon tissue invasion. Epithelial cell-intrinsic innate immune responses are essential to limit the invasion of both commensal and pathogenic bacteria and maintain beneficial host-bacterial relationships; however, little is known about the role of various cellular processes, notably autophagy, in controlling bacterial interactions with the intestinal epithelium in vivo. We demonstrate that intestinal epithelial cell autophagy protects against tissue invasion by both opportunistically invasive commensals and the invasive intestinal pathogen Salmonella Typhimurium. Autophagy is activated following bacterial invasion of epithelial cells through a process requiring epithelial cell-intrinsic signaling via the innate immune adaptor protein MyD88. Additionally, mice deficient in intestinal epithelial cell autophagy exhibit increased dissemination of invasive bacteria to extraintestinal sites. Thus, autophagy is an important epithelial cell-autonomous mechanism of antibacterial defense that protects against dissemination of intestinal bacteria.