This study aims to investigate the role of Streptococcus mutans–derived extracellular vesicles (SmEVs) in the progression of oral squamous cell carcinoma (OSCC). We integrated transcriptomics and DIA-based quantitative proteomics to systematically analyze changes in gene expression in CAL-27 cells after SmEV treatment, as well as the protein composition of SmEVs. Our findings demonstrate that SmEVs significantly activate the Wnt/β-catenin signaling pathway, and several vesicular proteins with potential β-catenin interactions were identified. In vivo experiments further confirmed that SmEVs promote tumor growth. This project provides a proteomic dataset of SmEVs in OSCC progression, offering a new molecular resource for understanding microbe–host interactions in cancer.