Circulating tumour DNA (ctDNA) is a promising minimally invasive biomarker for monitoring treatment response in cancer patients. In this study, we developed a tumour-informed workflow to enhance the detection of recurrence in head and neck cancer (HNC) patients, addressing challenges of low ctDNA tumour fractions and heterogeneity. Patient-derived tumour tissues (N = 12), peripheral blood cells, and 41 blood samples at baseline and post-treatment (3, 6, 12 and 24 months) were collected. Tumoral DNA and germline DNA underwent whole exome sequencing to identify somatic mutations, enabling the creation of individualized assays targeting up to 150 variants per patient. Supernatants from two HNC cell lines (CAL27 and SCC15) were used to evaluate assay sensitivity, which detected ctDNA levels as low as 2 parts in 100,000. Baseline ctDNA was detectable in all patients (100%, 12/12). While baseline ctDNA mutations did not predict outcomes, post-treatment ctDNA strongly correlated with disease progression. A ctDNA threshold of 1 part in 10,000 distinguished relapse events from non-relapse cases. Patients with ctDNA positivity at 3- and 6-month follow-ups had poorer event-free survival. Our tumour-informed ctDNA workflow demonstrates high analytical sensitivity and specificity, offering a transformative approach for HNC management by enabling treatment de-escalation based on precise response measurements.