Patients with ulcerative colitis (UC) often loss responses over long term usage of conventional therapies. Tofacitinib, a pan-Janus kinases (JAK) inhibitor is approved for moderate to severe UC treatment, while dose-limiting systemic side effects including infections, cancers and lymphoma limit its popularity of clinical application. This study sought to construct an anti-mucosal vascular addressin cell-adhesion molecule-1 (anti-MAdCAM-1) antibody modified reactive oxygen species (ROS) responsive human serum albumin-based nanomedicine denoted as THM, to improve the therapeutic efficacy of tofacitinib for UC treatment. THM has the drug releasing properties in response to ROS stimulation. In vitro studies show that THM selectively adhered to the endothelial cells and had obvious anti-inflammatory effect on macrophages. Meanwhile, the nanomedicine can inhibit the phenotypic switching of M1 macrophages and promote M2 polarization to produce anti-inflammatory medicators during wound healing. In addition, in vivo fluorescence imaging verified that THM exhibited enhanced preferential accumulation and extended retention in inflamed colon. Moreover, THM significantly reduced the production of proinflammatory cytokines in the colon and suppressed the homing of T cells to the gut in dextran sodium sulfate induced experimental colitis. This work elucidates that the inflamed colon-targeted delivery of tofacitinib by nanomedicine is promising for UC treatment and sheds light on addressing the unmet medical need.