The poor prognosis of head and neck cancer (HNC) is largely associated with the presence of metastasis in the lymph nodes (LN). Herein, the proteome of 140 multisite samples from a 59-HNC patient cohort, including primary and matched LN tissues, saliva, and blood cells, reveals insights into the biology and potential metastasis biomarkers that may assist in clinical decision making. The protein profiles are strictly associated with immune modulation across datasets, which provided the basis to investigate immune markers associated with metastasis. The proteome of LN metastasis cells quite recapitulates the proteome of primary sites. Conversely, the LN microenvironment proteome highlights candidate markers. By integrating selected markers at peptide, protein, and transcript levels with machine learning models, we indicate a nodal metastasis signature in blood and saliva. In summary, we present the deepest proteome characterization of multiple sampling sites in HNC, providing a promising basis to understand tumoral biology and indicating metastasis-associated biomarkers.