BACKGROUND: Drug-related deaths (DRDs) are a major public health challenge in the UK, but cross-national comparison is complicated by differences in mortality definitions and reporting systems.

METHODS: We analysed mortality data across the four UK countries to examine trends in mortality burden, geography, age, sex, deprivation, and substance involvement from 2000, using analysis-specific harmonisation to maximise comparability. Joinpoint regression characterised national mortality trends.

RESULTS: DRD rates increased across all countries. Scotland had the highest age-standardised rates throughout, peaking at 27.9 per 100,000 in 2020. The 2001-2023 average annual percentage change (AAPC) was lower in England (2.3%) than in Wales, Scotland and Northern Ireland (4.0-4.6%). Segment-specific APCs showed a decline in England to 2011, followed by an increase; a steeper increase in Wales from 2020; a sharp rise in Scotland during 2015-2019, followed by a decline; and an increase in Northern Ireland to 2021, followed by a non-significant decline. A stepwise deprivation gradient was present in all countries. Opioids remained dominant, while cocaine and gabapentinoid involvement increased across all countries; benzodiazepines were especially prominent in Scotland and Northern Ireland. Novel psychoactive substance involvement increased markedly in Scotland. Specific-substance recording was more complete in Scotland, while polysubstance involvement was prominent but reporting remained patchy and non-harmonised across the UK.

CONCLUSION: DRDs increased substantially across the UK, with marked geographic and socioeconomic inequalities and increasingly complex substance patterns. A UK-wide perspective highlights shared and country-specific features and supports targeted responses in high-burden places and groups, alongside improved surveillance and more complete mortality data.