The prognosis of locoregionally-advanced head and neck squamous cell carcinoma (LA-HNSCC) remains poor despite curative-intent multimodality treatment, with up to 50% of patients relapsing within the first 3 years. There is an urgent need for prospectively validated prognostic and predictive non-invasive biomarkers that allow for a better risk-stratification and a personalized treatment and surveillance. This review explores the emerging role of non-invasive biomarkers in LA-HNSCC, including circulating tumor DNA (ctDNA), inflammatory markers, nutritional indicators, and microbiome. ctDNA is one of the most promising approaches to detect minimal residual disease and to predict recurrence, particularly in HPV-related tumors. Inflammatory blood biomarkers, such as neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio, have consistently shown associations with prognosis in several retrospective studies, but prospective validation to avoid bias is needed. Nutritional biomarkers, including the Glasgow Prognostic Score and sarcopenia, reflect the severity of systemic inflammation and nutritional status, impacting on treatment outcomes and toxicity. Additionally, the microbiome’s influence on tumor development and response to anticancer therapies is emerging as a novel avenue that deserves further investigation. Integrating these non-invasive biomarkers into clinical practice has the potential to enhance prognostic accuracy, monitor treatment response, and guide personalized therapeutic strategies for improved outcomes in HNSCC patients. Further research and validation in larger cohorts and clinical trials are crucial for their widespread clinical adoption.