It is of great significance to eliminate excessive reactive oxygen species (ROS) for treating inflammatory bowel disease (IBD). Herein, for the first time, a novel nanozyme NiCo 2 O 4 @PVP is constructed via a step-by-step strategy. Noticeably, the existence of oxygen vacancy in the NiCo 2 O 4 @PVP is helpful for capturing oxygenated compounds, while both redox couples of Co 3+ /Co 2+ and Ni 3+ /Ni 2+ will offer richer catalytic sites. As expected, the obtained NiCo 2 O 4 @PVP exhibits pH-dependent multiple mimic enzymatic activities. Benefiting from the introduction of polyvinylpyrrolidone (PVP), the NiCo 2 O 4 @PVP possesses good physiological stability and excellent biosafety in stomach and intestines' environment. Meanwhile, the NiCo 2 O 4 @PVP also presents strong scavenging activities to ROS in vitro, including • O 2 − , H 2 O 2 , as well as • OH. Furthermore, a dextran sodium sulfate (DSS)-induced colitis model is established for evaluating the anti-inflammatory activity of NiCo 2 O 4 @PVP in vivo. Based on the size-mediated and charge-mediated mechanisms, the nanozyme can pass through the digestive tract and target the inflamed site for oral-administrated anti-inflammatory therapy. More interestingly, compared with the model group, the expression levels of inflammatory factors (e.g., Interleukin-6 (IL-6), Interleukin-1𝜷 (IL-1𝜷), tumor necrosis factor-𝜶 (TNF-𝜶), and inducible nitric oxide synthase (iNOS)) in colon of mice show a significant decrease after nanozyme intervention, thereby inhibiting the development of IBD. In short, current work provides an alternative therapy for patients suffering from IBD.