Radiation‐induced colitis is a serious clinical problem worldwide. However, the current treatment options for this condition have limited efficacy and can cause side effects. To address this issue, we developed colon‐targeted fullerenol@pectin@chitosan gel microspheres (FPCGMs), which can aggregate on colon tissue for a long time, scavenge free radicals generated in the process of radiation, and regulate intestinal flora to mitigate damage to colonic tissue. First, FPCGMs exhibit acid resistance and colon‐targeted release properties, which reduce gastrointestinal exposure and extend the local colonic drug residence time. Second, fullerenol, which has a superior scavenging ability and chemical stability, reduces oxidative stress in colonic epithelial cells. Based on this, we found that FPCGMs significantly reduced inflammation in colonic tissue, mitigated damage to tight junctions of colonic epithelial cells, and significantly relieved radiation‐induced colitis in mice. Moreover, 16S rDNA sequencing results showed that the composition of the intestinal flora was optimized after FPCGMs were utilized, indicating that the relative abundance of probiotics increased while harmful bacteria were inhibited. These findings suggest that it is a promising candidate for treating radiation‐induced colitis.This article is protected by copyright. All rights reserved