Head and neck squamous cell carcinoma (HNSCC) remains a major clinical challenge, with lymph node (LN) metastasis as the strongest predictor of poor survival. Current staging methods fail to capture the biological drivers of metastasis, underscoring the need for improved biomarkers. Extracellular vesicles (EVs), particularly small EVs (SEVs), have emerged as critical mediators of tumor progression and promising tools for non-invasive monitoring. Using an immune-competent orthotopic oral carcinoma model, we disrupted SEV biogenesis by knocking out the endosomal protein HRS in MOC2 cells. This intervention markedly reduced LN metastasis, angiogenesis, neural outgrowth, and reshaped immune infiltration in the tumor microenvironment. Integrating proteomics, patient plasma-SEV profiling, and histological analyses, we identified five SEV-associated proteins, SYT1, STXBP1, TGFβ1, ALCAM, and ITGA5 linked to angiogenesis, ECM remodeling, immune modulation, and perineural invasion. Our findings establish SEVs as functional drivers of metastasis and highlight their potential both as therapeutic targets and as liquid biopsy biomarkers to improve risk stratification and precision treatment in HPV-negative HNSCC.