Results concerning a potential preventive effect of aspirin on head and neck cancer (HNC) are conflicting. We examined the association between low-dose aspirin use and HNC risk overall and by degree of human papillomavirus association in a nested case–control study using nationwide registries. Cases (n = 12 389) were all Danish residents diagnosed with primary HNC (2000–2015). Age- and sex-matched population controls (n = 185 835) were selected by risk-set-sampling. Using conditional logistic regression, we estimated multivariable-adjusted odds ratios and 95% confidence intervals for HNC associated with low-dose aspirin use (≥2 prescriptions). No association was observed between low-dose aspirin ever-use and overall HNC (odds ratio: 1.03, 95% confidence interval: 0.97–1.10). Estimates remained neutral according to patterns of use. Low-dose aspirin use appeared to slightly decrease HNC risk among the eldest (71–84 y), independently of human papillomavirus association, while slightly increase HNC risk among younger age groups (30–60, 61–70 y), driven by an increased risk of oral cancer. However, no consistent patterns in risk estimates were found according to duration and consistency of low-dose aspirin use in the age-stratified analyses.