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Cancer patients commonly experience high levels of psychological stress, which poses significant risks to their well-being. Radiotherapy is a primary treatment modality for cancer; however, it often leads to intestinal injuries in these patients. Nevertheless, the impact of mental stress on radiotherapy-intertwined complications remains unclear. To induce intestinal injury, we employed total abdominal irradiation in our experimental model. We conducted high-throughput sequencing to analyze the expression profile of miRNAs in the hippocampus. We observed that mice with depression exhibited more severe intestinal injuries following total abdominal irradiation. Remarkably, oral administration of Marasmius androsaceus not only alleviated the depressive phenotype but also mitigated radiation-induced intestinal toxicity. Notably, this radioprotective effect was not observed in mice without depression. Depression disrupted the hippocampal miRNA expression profile in mice subjected to local irradiation of the abdomen, leading to the accumulation of miR-139–5p and miR-184–3p in the hippocampus, serum, and small intestine tissues. However, treatment with Marasmius androsaceus reprogrammed the miRNA expression signature in mice with depression. Furthermore, intravenous injection of antagomirs targeting miR-139–5p and miR-184–3p ameliorated depression, up-regulated Spn expression, reduced radiation enteritis, and improved the integrity of the small intestine in irradiated mice. Our findings demonstrate the efficacy of Marasmius androsaceus , a small mushroom, in alleviating depression-aggravated intestinal toxicity following radiotherapy by reprogramming hippocampal miRNA expression. [Display omitted] • Depression aggravates intestinal radiation injury in mouse models. • Marasmius androsaceus mitigates intestinal toxicity in depression-afflicted mice. • Marasmius androsaceus reprograms the hippocampal miRNA expression. • Marasmius androsaceus mitigates radiation injury in a miRNA-dependent manner. [ABSTRACT FROM AUTHOR]