<p>Yacon concentrate, which is rich in fructan, phenolic compounds, and flavonoids, exhibits notable nutritional and antioxidant properties. This study explored the potential of New Zealand yacon concentrate to modulate the gut microbiota and host metabolism, alleviate inflammation, and enhance antitumor immunity. The anti-inflammatory and antitumor effects of yacon concentrate were evaluated in mouse models of dextran sulfate sodium (DSS)-induced colitis and colorectal cancer (CRC). Ex vivo gut chemostat model experiments were performed to assess the impact of yacon concentrate on human gut microbiota remodeling. The gut microbiota composition was then analyzed via metagenomic sequencing, and metabolomic profiling was conducted to identify the key bioactive metabolites. Yacon concentrate significantly ameliorated DSS-induced colitis by reducing weight loss, lowering the disease activity index scores, and alleviating colonic shortening in mice. In CRC models, yacon concentrate markedly suppressed tumor growth, reduced tumor incidence, and decreased tumor burden. Microbiota derived from the chemostat after yacon supplementation not only enriched beneficial bacteria and inhibited the growth of immunotherapy-resistant bacteria but also enhanced energy and short-chain fatty acid metabolism. Moreover, transplantation of this microbiota into mice significantly improved the tumor microenvironment and inhibited tumor growth. Collectively, these findings indicate that yacon concentrate is associated with changes in the gut microbiota and metabolomic profiles, supporting a potential link between yacon intake and modulation of the gut microbiota–metabolome axis. These observations provide a rationale for further mechanistic and interventional studies evaluating yacon concentrate as a dietary strategy for colitis prevention and CRC prevention, and as an adjunctive treatment.</p>