Similar to the US, mortality due to suicide and the use of opioids, alcohol, and other substances (so-called "Deaths of Despair"), is rising in Canada and has been disproportionately observed among Whites compared to other racial and ethnic groups. This study aimed to assess the determinants of the ethno-racial differences in the use of substances that underlie these deaths. Using nationally representative data from the Canadian Community Health Survey (2003, 2015-2016, 2018 cycles), a decomposition analysis was performed to estimate the contribution of psychosocial determinants, including age, sex, marital status, immigration, education, income, rurality, and affective health on inequalities between White and non-White populations in illicit substance, opioid, and problematic alcohol use and combined use (≥ 2) of substances. Overall, White respondents reported higher levels (by 5% to 10%) of substance use than non-White peers. Over 30% of the ethno-racial inequalities in illicit substance, problematic alcohol, and polysubstance use are explained by the protective role of immigration among those who are not White, whose low levels of substance use lower the prevalence in the non-White population overall. Among those born in Canada, no ethno-racial differences in substance usewere observed. Social determinants, particularly immigrant status, explain a substantial proportion of ethno-racial inequalities in substance use in Canada. The jump in substance use between racialized populations who immigrated to Canada and those Canadian-born highlights the importance of exploring within-group variability in deaths of despair risk and considering how intersecting forces including systemic racism shape substance use patterns across generations.