This article explores the factors contributing to drug-related deaths in English and Welsh prisons between 2015 and 2020. Based on content analysis of all Prison and Probation Ombudsman ‘other non-natural’ fatal incident investigation reports, descriptive statistics were generated. Qualitative analysis explored the circumstances surrounding deaths and key risk factors. Most deaths were of men, whose mean age was 39 years. Drug toxicity was the main factor in causing death, exacerbated by underlying physical health conditions and risk-taking behaviours. A variety of substances were involved. New psychoactive substances became more important over time. A high proportion had recorded histories of substance use and mental illness. During this period, the prison system was under considerable stress creating dangerous environments for drug-related harm. This study highlights the process of complex interaction between substances used, individual characteristics, situational features and the wider environment in explaining drug-related deaths in prisons. Implications for policy and practice are discussed.