Oral antibiotics can influence cancers and immunotherapy by interfering with the intestinal microbiota. However, the association between oral antibiotics and oral squamous cell carcinoma (OSCC) as well as the mechanisms underlying the effects of oral antibiotics on OSCC remain unclear. Here, we found that oral antibiotics cocktail (4Abx) promoted the tumor development and shifted the microbiota, decreasing the abundance of probiotic bacteria, and altered microbial metabolism in the gut of OSCC mice, increasing tyrosine and decreasing glutamate levels. In vitro experiments showed that tyrosine upregulated the PD-1 expression in T cells, SCC7 cell proliferation, and necroptosis expression. IL-10 expression level in CD11c+?cells was reduced by glutamate. Furthermore, the expression of the necroptosis-related proteins, including receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like (MLKL), was higher in the OSCC mice treated with 4Abx. Supplementation with glutamate or healthy mouse feces by gavage alleviated the tumor-promoting effect of 4Abx with restored balance of microbial metabolism. Overall, we identified the detrimental role of oral antibiotics in promoting OSCC development through altered intestinal microbiota, microbial metabolism, and immune dysbiosis, implying the need for antibiotic stewardship in OSCC treatment.