To describe longitudinal trends in the prevalence of mental distress across the first year of the COVID-19 pandemic (April 2020‒April 2021) among US women at the intersection of sexual orientation and racialized group. Participants included 49 805 cisgender women and female-identified people from the COVID-19 Sub-Study, a cohort of US adults embedded within the Nurses' Health Studies 2 and 3 and the Growing Up Today Study. We fit generalized estimating equation Poisson models to estimate trends in depressive and anxiety symptoms by sexual orientation (gay or lesbian, bisexual, mostly heterosexual, completely heterosexual); subsequent models explored further differences by racialized group (Asian, Black, Latine, White, other or unlisted). Relative to completely heterosexual peers, gay or lesbian, bisexual, and mostly heterosexual women had a higher prevalence of depressive and anxiety symptoms at each study wave and experienced widening inequities over time. Inequities were largest for sexual minority women of color, although confidence intervals were wide. The COVID-19 pandemic may have exacerbated already-glaring mental health inequities affecting sexual minority women, especially those belonging to marginalized racialized groups. Future research should investigate structural drivers of these patterns to inform policy-oriented interventions. (. 2024;114(5):511-522. https://doi.org/10.2105/AJPH.2024.307601).