Ulcerative colitis (UC) is a chronic, non-specific inflammatory disorder of the intestines whose etiology is influenced by various factors. Intestinal barrier impairment due to disturbances in the intestinal microenvironment is a key feature of UC. Current therapeutic strategies are constrained in their capacity to fully restore the intestinal barrier and achieve comprehensive resolution of inflammation in a coordinated manner. In this study, we constructed a pterostilbene (PSB)-loaded prebiotic microcapsule (PSB@MC) using a microfluidic electrospray method and characterized it using various means. Its safety, biodistribution, protective, and therapeutic effects on colitis were evaluated in various animal models. The potential mechanisms by which PSB@MC exerts its therapeutic effects were subsequently explored. The results indicated that PSB@MC exhibited favorable biocompatibility and facilitated targeted delivery of PSB to the colon. Moreover, the wrinkled morphology of PSB@MC contributed to prolonged drug retention in the colon. Oral PSB@MC administration restored intestinal microenvironment homeostasis by scavenging reactive oxygen species (ROS), decreasing pro-inflammatory cytokines, modulating gut microbiota and metabolism, and providing protective and therapeutic benefits against dextran sulfate sodium-induced colitis. Additionally, our research demonstrated that PSB@MC could activate the aryl hydrocarbon receptor/interleukin-22 (AHR/IL-22) pathway to enhance the integrity of the intestinal barrier. These results suggest that PSB@MC could be a new, secure, and efficient UC therapy option.