(1) Background: Colorectal cancer (CRC) is a leading cause of cancer mortality worldwide. The tumor microenvironment (TME) is a key driver of disease progression, shaping both pro- and anti-tumor immune responses. Interleukin-1β (IL-1β) is a pleiotropic pro-inflammatory cytokine that participates in both homeostatic and pathological conditions. It has been shown to be upregulated in many tumors, including CRC, where it promotes angiogenesis, immunosuppression, and resistance to chemotherapy. (2) Objective: Elucidate the correlation between TME IL-1β and colon microbiotic changes during CRC progression and approach inhibition of IL-1β as a therapeutic strategy in combination with chemotherapy. (3) Design: Using an orthotopic mouse model of CRC, we compared tumor growth, metastatic spread, immune infiltration and microbiome composition in control and IL-1β knockout mice. In addition, we studied the effects of IL-1β neutralization alone or in combination with FOLFOX chemotherapy on CRC prognosis. (4) Results: IL-1β promoted CRC progression by enhancing pro-inflammatory signalling, recruiting immunosuppressive myeloid cells, and driving microbiome dysbiosis. In contrast, IL-1β deficiency increased antigen-presenting myeloid cells and CD⁸⁺ T-cell infiltration, leading to delayed tumor growth and reduced metastasis. FOLFOX chemotherapy alone exacerbated systemic and local inflammation, facilitating liver metastasis. Strikingly, the addition of IL-1β blockade abrogated FOLFOX-induced inflammation, enhanced anti-tumor immunity, and prevented metastatic spread. (5) Conclusions: IL-1β from the TME links microbiome dysbiosis, tumor-promoting inflammation and poor chemotherapy outcomes in CRC. Combining IL-1β inhibition with standard FOLFOX chemotherapy represents a promising therapeutic approach to improve prognosis in CRC patients.