Aims: Antihistamines are routinely taken to control allergic reactions or sedation to induce sleep. There are, however, growing concerns regarding sedating antihistamine misuse. This research aims to evaluate deaths related to antihistamines in England occurring during 2000–2019. Methods: Cases reported to the National Programme on Substance Abuse Deaths from England occurring in 2000–2019 with antihistamine detections at postmortem were extracted for analysis. Results: In total, 1666 antihistamine postmortem detections were identified from 1537 cases. Sedating antihistamines available for purchase under pharmacist supervision but without need for a prescription (pharmacy-only medications) were present in a significant majority of cases (85.2%, P <.01). Despite an increasing trend for antihistamine-related deaths over time, the proportion of deaths where an antihistamine was implicated declined over the same period. Specific concerns with regards to the misuse of these pharmacy-only sedating antihistamines are raised with regards to the significant proportion of cases that were concluded as suicide (20.9%, P <.01), and the high prevalence of their use in combination with other central nervous system depressants (94.8% of cases). Conclusion: This is the first report in over 40 years regarding antihistamine-related mortality from England. The rising trend in sedating antihistamine-related deaths may be contributed to by their increasing availability and the perceived negligible dangers associated with antihistamines, both from the general public and learned professionals. Awareness of the dangerous sedative properties that some antihistamines possess is, however, heightened in individuals deliberately seeking these effects. Urgent review of sedating antihistamines currently assigned under the pharmacy-only classification is needed to achieve antihistamine harm reduction.