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In the USA, Black women aged 25–44 years are disproportionately murdered compared with their White counterparts. Despite ongoing efforts to reduce racial and structural inequities, the result of these efforts remains unclear, particularly in light of the COVID-19 pandemic. This study examined a cross-sectional time series of homicide death rates, by race, from the Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research system. We included data for women aged 25–44 years between 1999 and 2020 among 30 states in the USA. Homicide death was classified using underlying cause and multiple cause of death codes; mortality rates were calculated per 100 000 based on US Census Bureau population sizes. Homicide methods were classified as firearm, cutting or piercing, and other. Firearm homicides were compared with other homicides with logistic regression including covariates of race, time, and their interaction. We report odds ratios and 95% CIs. In 2020, the homicide rate among Black women was 11·6 per 100 000, compared with 3 per 100 000 among White women. This inequity has persisted over time and is virtually unchanged since 1999. Homicide inequities vary across US states; in 11 states, racial inequities have increased since 1999. The racial inequity was greatest in Wisconsin, where in 2019–20, Black women aged 25–44 years were 20 times more likely to die by homicide than White women. Homicide by firearm is increasing in frequency; women in the USA had 2·44 (95% CI 2·14–2·78) times the odds of homicide involving firearms in 2019–20 compared with 1999–2003. Firearm homicide deaths are disproportionately concentrated among Black women in every region in the USA. Our findings suggest that there is an urgent need to address homicide inequities among Black and White women in the USA. Enacting federal legislation that reduces gun access is a crucial step. Policy makers must address long-standing structural factors that underpin elevated gun violence by implementing sustainable wealth-building opportunities; developing desegregated, mixed income and affordable housing; and increasing green spaces in communities where Black women largely reside. National Institute of Mental Health of the National Institutes of Health. [ABSTRACT FROM AUTHOR]