Immigrant young adults from predominantly people of color countries (IYPOC) encounter structural stressors that potentially exacerbate health outcomes such as substance use amidst ongoing societal challenges. The association may be further compounded by cultural isolation and the dual task of identity negotiation. The current study explored cultural isolation as a mediator of the association between racial discrimination and substance use among IYPOC. A cross-sectional online survey was conducted to collect data from IYPOC residing in the United States. The analytic sample was composed of 262 individuals aged 18 to 29, and the largest racial group was Black or African American. The current study performed regressions and PROCESS Macro Model 4 with bootstrapping. Racial discrimination and cultural isolation were statistically significantly associated with substance use. The indirect effect of racial discrimination on substance use through cultural isolation was statistically significant. The results underscore the need for tailored support and interventions that address the complex interplay of racial discrimination, cultural isolation, and health outcomes among IYPOC.