This study aimed to examine the association between the use of H1-antihistamines (AHs) and head and neck cancer (HNC) risk in patients with type 2 diabetes mellitus (T2DM). Data from the National Health Insurance Research Database of Taiwan were analyzed for the period from 2008 to 2018. A propensity-score-matched cohort of 54,384 patients each in the AH user and nonuser groups was created and analyzed using Kaplan-Meier method and Cox proportional hazards regression. The results showed that the risk of HNC was significantly lower in AH users (adjusted hazard ratio: 0.55, 95% CI: 0.48 to 0.64) and the incidence rate was also lower (5.16vs. 8.10 per 100,000 person-years). The lower HNC incidence rate in AH users (95% CI: 0.63; 0.55 to 0.73) suggests that AH use may reduce the risk of HNC in T2DM patients.