Oxymatrine (OMT), an alkaloid derived from the root of the Sophora flavescens, has been reported to possess a significant effect on relieving UC owing to its anti-inflammatory property. But the other therapeutic mechanism of OMT remains unclear. Recent studies have found, PI3K/AKT signaling pathway is involved in the pathogenesis of UC by pro-inflammatory effects and activating T cells. Moreover, PI3K/AKT pathway is one of the most important pathways for regulating cell apoptosis. Thus, we aim to explore whether OMT protects against UC by targeting PI3K/AKT pathway. We established the UC mice models, using LY294002 (a specific inhibitor of PI3K/AKT) as a positive control, to observe the effect of low, medium and high dose of OMT on UC and its influence on PI3K/AKT signaling pathway. Our data indicated that OMT can significantly ameliorate UC through anti-inflammatory, pro-apoptotic, down-regulating the differentiation of Th1 and Th17 cells via PI3K/AKT pathway. This study reveals that PI3K/AKT signaling pathway is a potential mechanism of OMT-induced UC remission and suggests that OMT is a promising therapeutic agent for the treatment of UC.