Characterized by elevated reactive oxygen species (ROS) and disrupted gut flora, ulcerative colitis (UC) affects millions of patients worldwide. Probiotic therapy is commonly utilized in clinical practice to modulate intestinal flora and ameliorate colitis symptoms. Nonetheless, oral probiotics encounter challenges such as limited bioactivity, brief retention time, intricate pathological conditions, and singular efficacy. Here we designed plant-derived 18β-glycyrrhetinic acid (18β-GA) prodrug nanomicelles with ROS and inflammation-resolving capabilities, as well as anti-depressant effects, to protect probiotics and amplify their therapeutic effects in alleviating UC and UC-associated depression-like behaviors. Upon oral administration to UC lesion sites, prodrug nanomicelles can be dissociated by excessive ROS and release 18β-GA to attenuate colonic inflammatory responses and oxidative stress, which in turn provided a favorable microenvironment for LGG to repair intestinal barrier integrity and restore the gut microbiota. The synergistic therapeutic effects of STG nanomicelles and LGG alleviated UC-associated depression-like behavior by suppressing the activation of microglia and reducing neuroinflammation. This study introduces a promising strategy for oral nanomedicine with satisfactory therapeutic outcomes for the treatment of inflammatory diseases by integrating naturally derived small-molecule drugs with probiotics.