Objective: Recognizing discrimination as a significant public health risk during the coronavirus disease 2019 (COVID-19) pandemic, which coincided with increased drug use and heightened awareness of structural disparities in the United States, we investigated its association with the odds of drug use in a large and diverse cohort from the All of Us Research Program. Methods: In this cross-sectional study, data from 68,976 participants completed the COVID-19 participant experiences (COPE) survey. We applied logistic regression models with propensity score-based overlap weighting to examine associations between everyday discrimination and drug use. Self-reported everyday discrimination score and drug use were the primary exposure and outcome measures, respectively. Results: Of the 67,662 COPE respondents (mean [standard deviation] age, 57.5 [15.9] years; female sex at birth, 43,658 [64.5%]), we identified 15,493 participants with no reported discrimination and 15,493 participants with reported discrimination, after overlap weighting. The odds of drug use in those who reported discrimination was 1.38 (95% confidence interval, 1.32–1.43), with a dose-dependent association based on discrimination score. Participants who experienced discrimination had significantly higher odds of using drugs and this association was particularly pronounced in those under 40 years of age, those assigned female sex at birth, current smokers, individuals undergoing chemotherapy or immunotherapy, and those experiencing unemployment or COVID-19/flu-like symptoms. Conclusion This relationship was observed across various types of drugs and different reasons for discrimination, and it was particularly pronounced in specific subgroups. These findings provide critical evidence for developing targeted preventive interventions; however, further longitudinal studies for causality are warranted.