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Simple Summary: Weaning stress is a major problem in the pig industry, causing high rates of diarrhea and poor performance in piglets. Cardamonin is a bioactive plant extract that possesses anti-inflammatory, anti-oxidant, and anti-viral properties. In this experiment, we investigated the effect of Cardamonin on intestinal barrier damage and inflammatory response caused by immune stress in piglets by establishing a stress model of LPS. Compared with those of the LPS group, the intestinal mucosal morphology and expression of tight junction proteins in the cardamonin group were improved, along with the inflammation response. Furthermore, certain intestinal microbiota and inflammation-related metabolites showed a significant correlation. The results indicate that the administration of Cardamonin can effectively improve intestinal mucosal barrier damage and inflammatory response induced by LPS by regulating the composition and metabolism of intestinal microbiota, with a better effect observed at a dosage of 6 mg/kg. The primary factor leading to elevated rates of diarrhea and decreased performance in piglets is immunological stress. The regulation of immune stress through the intestinal flora is a crucial mechanism to consider. In total, 30 weaned piglets were randomly allocated to five groups: the basal diet group (Control), basal diet + lipopolysaccharides group (LPS), basal diet + 250 μg/kg 6-Formylindolo [3,2-b] carbazole + LPS group (FICZ), basal diet + 3mg/kg Cardamonin + LPS group (LCDN), and basal diet + 6mg/kg Cardamonin + LPS group (HCDN/CDN). The results showed that compared with those of the LPS group, the expression of tight junction proteins (occludin; claudin-1) in the FICZ group was significantly increased, and the mRNA levels of IL-1β and TNF-α were significantly reduced (p < 0.05). HCDN treatment had a better effect on LPS-induced intestinal barrier damage in this group than it did in the LCDN group. HCDN treatment leads to a higher villus height (VH), a higher ratio of villi height to crypt depth (V/C), higher tight junction proteins (ZO-1; occludin), and higher short-chain fatty acids (SCFAs). In addition, correlation analyses showed that Succinivibrio was positively correlated with several SCFAs and negatively correlated with prostaglandin-related derivatives in the FICZ group and CDN group (p < 0.05). In summary, Cardamonin alleviates intestinal mucosal barrier damage and inflammatory responses by regulating the intestinal microbiota and its metabolism. [ABSTRACT FROM AUTHOR]