["Addiction, EarlyView. ", "\nAbstract\n\nBackground and aim\nRecent studies have shown that Black men and women have been disproportionately impacted by overdose deaths within recent years, with their mortality rates rising sharply compared with their White counterparts. As the United States is in the fourth wave of the polysubstance use overdose crisis, it is unclear if polysubstance use is contributing to these disparate patterns of overdose mortality across race and gender. This study aimed to measure gender‐specific racial disparities in opioid related polysubstance use drug mortality in the United States from 2004 to 2022.\n\n\nDesign, setting and participants\nIn this population‐level study of all deaths occurring in the United States, we obtained finalized death records of overdose fatalities identified using codes in the International Classification of Diseases, Tenth Revision (ICD‐10) from Centers for Disease Control (CDC) and Prevention's Wide‐Ranging Online Database for Epidemiologic Research (WONDER) Multiple Cause of Death file, from 2004 to 2022. Annual Percent Change (APC) and Annual Average Percent Change (AAPC) in age‐adjusted mortality rates (AAMR) for White men, White women, Black men, Black women, Hispanic men and Hispanic women were determined using joinpoint regression in this cross‐sectional study.\n\n\nMeasurements\nJoinpoint regression was used to examine mortality rates for opioid‐only, opioids with a stimulant, opioids with benzodiazepines, among racial/gender groups to measure temporal trends in age‐adjusted overdose mortality due to polysubstance‐related overdose.\n\n\nFindings\nThe final analytic sample included n = 627 793 opioid‐only deaths, n = 196 001 opioid‐stimulant and n = 117 322 opioid‐benzodiazepine overdose deaths. Opioid‐involved deaths increased across all groups, with the highest absolute rate change experienced by non‐Hispanic Black men (53.55 per 100 000, AAPC: 17.3%) and pronounced increases shown to occur between 2011 and 2022 (APC: 29.0%). Opioid‐stimulant polysubstance use deaths had the largest increases among non‐Hispanic Black men and women, with a 39.5% APC (2011–2022) for men and 36.2% APC (2012–2022) for women. Among Hispanic men, the rates accelerated 33.8% per year (2012–2022). For opioid‐benzodiazepine polysubstance use deaths, non‐Hispanic White men and women experienced the highest absolute rate change of 3.39 and 2.41 per 100 000, respectively.\n\n\nConclusions\nIn the United States from 2004 to 2022, overdose deaths from polysubstance use escalated sharply across all racial and ethnic groups, with disproportionate increases across non‐Hispanic Black and Hispanic individuals, particularly in opioid‐stimulant and opioid‐only profiles.\n\n"]