Ulcerative colitis (UC) is a chronic inflammatory bowel disease. In treatment with traditional chemotherapy, the drug lost its effectiveness due to the first bypass effect and acidic environments of the gastrointestinal tract (GI). It will be best to administer the oral therapeutic drug directly to the colonic tissue or at the site of inflammation to enhance the efficiency and reduce systemic toxicity of the drug. In this regard, nanotechnology plays a significant role in terms of targeted drug delivery systems. Targeted drug delivery for the treatment of UC is challenging due to physiological and biochemical barriers. Researchers are trying to tackle all obstacles in drug delivery with the latest advancements in nanotechnology. In this chapter, we have explained the pathophysiology of UC, and physiological and biochemical barriers in detail. Furthermore, we have compared a traditional treatment system with a targeted drug delivery system. In this regard, we have explained some latest advanced drug delivery systems to tackle UC such as smart drug delivery systems, pH-responsive drug delivery systems, microbial-based drug delivery systems, hydrogel-based drug delivery systems, ROS-responsive drug delivery system and osmotically regulated drug delivery system. In the preclinical setting, these advanced drug delivery systems have proven their potential in the management of UC. On the basis of facts and findings, we can say that nano-based targeted drug delivery may be a ray of hope for UC patients.