Oxymatrine (OM) is the biologically active ingredient of Chinese medicinal herb Sophora flavescens, which is reported to be effective on alleviating ulcerative colitis (UC) due to its anti-inflammatory property. However, its highly effective dose is an obstacles to its application. Therefore, liposome was used to encapsulate OM, realize targeting delivery to colitis and thus reduce drug dosage. Meanwhile, considering the potential anti-inflammatory ability of nitric oxide (NO), a NO donor, d-α-tocopheryl polyethylene glycol succinate nitrate (TN), was introduced into the liposomal system and OM loaded NO-releasing liposomes (OM@TN-lip) were prepared in order to co-deliver OM and NO to the inflammatory lesions of DSS-induced UC mice to achieve the combination therapy. OM@TN-lip was multilamelar sphere with the encapsulation efficiency of ~70%, the diameter of ~200 nm and ζ-potential of about -13 mV. Bio-distribution results revealed the liposomes could efficiently accumulate in the inflammatory colon by diffusion and maintain for more than 36 h. In UC mice model, OM@TN-lip showed significant alleviation of inflammation and the treatment was highly related to down-regulation of pro-inflammatory cytokines TNF-α, IFN-γ, IL-1β and IL-6, decrease of macrophages infiltration, activity decrease of myeloperoxidase (MPO) and cyclooxygenase-2 (COX-2), and rebuilding antioxidant/oxidation balance by reducing reactive oxygen species (ROS) and increasing Glutathione (GSH) in colon.