Background The UK and USA currently report their highest number of drug-related deaths since records began, with higher rates among individuals experiencing homelessness. Aims Given that overdose prevention in homeless populations may require unique strategies, we evaluated whether substances implicated in death differed between (a) housed decedents and those experiencing homelessness and (b) between US and UK homeless populations. Method We conducted an internationally comparative retrospective cohort study utilising multilevel multinomial regression modelling of coronial/medical examiner-verified drug-related deaths from 1 January 2012 to 31 December 2021. UK data were available for England, Wales and Northern Ireland; US data were collated from eight county jurisdictions. Data were available on decedent age, sex, ethnicity, housing status and substances implicated in death. Results Homeless individuals accounted for 16.3% of US decedents versus 3.4% in the UK. Opioids were implicated in 66.3 and 50.4% of all studied drug-related deaths in the UK and the USA respectively. UK homeless decedents had a significantly increased risk of having only opioids implicated in death compared with only non-opioids implicated (relative risk ratio RRR = 1.87, 95% CI 1.76-1.98, P < 0.001); conversely, US homeless decedents had a significantly decreased risk (RRR = 0.37, 95% CI 0.29-0.48, P < 0.001). Methamphetamine was implicated in two-thirds (66.7%) of deaths among US homeless decedents compared with 0.4% in the UK. Conclusions Both the rate and type of drug-related deaths differ significantly between homeless and housed populations in the UK and USA. The two countries also differ in drugs implicated in death. Targeted programmes for country-specific implicated drug profiles appear warranted.