BACKGROUND: Ulcerative colitis (UC) is a non-specific inflammatory bowel disease. Unlike any single form of cell death reported previously, macrophage PANoptosis, a unique programmed cell death characterized by inflammation and necrosis, plays a crucial role in the pathogenesis of colitis. Changdiqing Decoction (CDQD), an empirical hospital prescription enema, has been used to treat UC for decades. This study aimed to investigate the multi-target anti-colitic effects of CDQD by examining its impact on intestinal homeostasis and its anti-inflammatory properties. METHODS: A dextran sulfate sodium (DSS)-induced mouse model of acute colitis was employed. Interferon-gamma (IFN-gamma) and KPT-330 were used to induce macrophage PANoptosis. Ultra-high-performance liquid chromatography-high-resolution mass spectrometry (UHPLCHRMS) was utilized to identify the chemical constituents of CDQD. Multi-omics analysis and fecal microbiota transplantation (FMT) were used to explore the therapeutic targets and gut microbiota alterations induced by CDQD. RESULTS: CDQD treatment significantly alleviated colitis symptoms in mice, with a dose-dependent therapeutic effect. The decoction mitigated PANoptosis in colon tissues and bone marrow-derived macrophages (BMDMs). 16S rRNA sequencing analysis and metabonomics revealed that CDQD administration significantly altered the gut microbiota composition and metabolite profiles. Notably, CDQD-modulated gut microbiota exhibited anti-colitic effects through FMT. Integrated transcriptomics and network pharmacology analysis revealed that CDQD significantly downregulated the PI3K/Akt signaling pathway in colitis. This finding was further validated using the inhibitors LY294002 and MK2206. CONCLUSIONS: CDQD alleviates colitis by suppressing inflammatory macrophage activation and modulating the gut microbiota. Our research provides a novel traditional Chinese medicine strategy for the treatment of UC via enema administration.