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Colorectal cancer (CRC) is both a leading cause of cancer-related mortality and one of the most frequently diagnosed cancers. Previous studies have shown that zearalenone and theabrownin each exert anti-CRC effects. Here, we aimed to evaluate the anti-tumor properties of theabrownin and zearalenone mixture (TZ) and to assess whether supplementing TZ with 5-FU, a commonly used chemotherapeutic drug, could further suppress CRC tumorigenesis. Our results revealed that TZ significantly attenuated AOM/DSS-induced colorectal tumorigenesis. TZ improved survival rate, reduced tumor count, preserved colon length, and mitigated colonic inflammation in AOM/DSS mice. In addition, the concentration of pro-inflammatory cytokines IL-6, TNF-α and IL-17 A/F and proliferative PI3K/AKT were significantly reduced. Metagenomic analyses revealed that TZ modulated the gut microbiota and mycobiota composition and increased the fecal acetate and propionate levels. Furthermore, the enrichment of the bacterial Desulfovibrionaceae bacterium LT0009, Helicobacter sp. MIT 03-1616 and fungal Xylariaceae sp. FL0594 was associated with the reduction of tumor multiplicity and pro-inflammatory cytokines. No additional benefits were observed with combining TZ with 5-FU. Taken together, TZ presented remarkable inhibitory effects on colorectal tumorigenesis, indicating its potential as a novel therapeutic candidate for CRC.