Objectives. To compare substance use among Asian American adults in 2020, when anti-Asian violence increased, with substance use among the same group during the previous 4 years and compare this with that of non-Hispanic Whites. Methods. Using data from the National Survey on Drug Use and Health, 2016 to 2020, we investigated changes in substance use among Asian Americans compared with non-Hispanic Whites before and during the COVID-19 pandemic. We performed difference-in-difference analyses to estimate adjusted changes in past-month substance use in the 2 groups. Results. The incidence rate ratio (IRR) among Asian Americans' past-month alcohol use, cocaine use, and tranquilizer misuse in 2020 versus in 2016 to 2019 was 1.3 times, 3.0 times, and 17.2 times, respectively, the same IRR among Whites. Conclusions. The significant increase in misuse of several substances among Asian Americans relative to Whites in 2020 calls for careful assessment, identification, and treatment of this understudied population group. Public Health Implications. Besides increasing Asian substance users' access to socioculturally responsive treatment programs, policy and resources should be focused on multilevel violence prevention efforts such as antiracial discrimination public education programs. (Am J Public Health. 2023;113(6):671-679. https://doi.org/10.2105/AJPH.2023.307256).