OBJECTIVES: This study explores the drug use behaviour in the US general population in the early days of the COVID-19 pandemic with a focus on the relationship between sociopsychological factors, mobility restrictions from March to June 2020 and mental health conditions. DESIGN: A retrospective anonymous online survey representing a cross-section of the US population in 2020. SETTING: A qualified panel of 500 000 Qualtrics participants stratified by gender, race, age and geographical region to represent the US population. PARTICIPANTS: 3340 participants voluntarily consented to respond. MEASURES: Outcome measure for illicit and non-medical use of prescription drugs based on the National Institute on Drug Abuse-Modified Alcohol, Smoking and Substance Involvement Screening Test Level-2 Substance Use for Adult Questionnaire and predictor measures include self-reports of mobility behaviours, demographics and mental states using psychometrically validated scales. RESULTS: χ CONCLUSIONS: Mobility restriction was a risk factor for drug use. Demographics and mental health conditions were important covariates, underscoring the need for further research on unintended consequences of infection control policies during national health crises.