As one of the most common inflammatory bowel diseases (IBDs), ulcerative colitis (UC) has become a rising global health issue that affects people's quality of life. Conventional therapeutic drugs have low bioavailability and may cause serious side effects due to their lack of acidic resistance and lesion-targeting capabilities. The development of novel nanomedicines to overcome these problems is urgently needed. Nanozymes have attracted attention because of their excellent catalytic efficiency in various harsh environments. In this study, tannic acid-vanadium (TA-V) nanozymes with multienzymatic and excellent antioxidant abilities, which exhibit acidic resistance and a negative surface charge, were successfully developed. All these characteristics make it possible that these nanozymes are not easily decomposed by gastric acid and can effectively accumulate in colitis lesions with a positive charge through oral delivery. In vitro and in vivo experiments further demonstrated the excellent prophylactic and therapeutic value of these compounds in the treatment of UC by scavenging reactive oxygen/nitrogen species (ROS/RNS) and mitigating the oxidative stress environment, thus downregulating the levels of the proinflammatory cytokines IL-1β, IL-6, and TNF-α. Furthermore, TA-V also showed excellent biosafety and biocompatibility without causing obvious damage to the main organs. This work provides novel preventative and therapeutic TA-V nanozymes that might have potential clinical applications in UC treatment.