Background: Unpaid caregivers for adults play critical roles in health care systems by providing care to older adults and those with chronic conditions. The COVID-19 pandemic has heightened the need for care, forcing some into caregiving roles and disrupting others. Research is needed to estimate the prevalence of caregiving and identify factors associated with adverse mental health.Methods: In June 2020, Internet-based surveys with questions about demographics, caregiving responsibilities, and mental health were administered to US adults aged ≥18 years. Demographic quota sampling and survey weighting to improve cross-sectional sample representativeness of age, gender, and race/ethnicity. Prevalence ratios for adverse mental health symptoms were estimated using multivariable Poisson regressions.Findings: Of 9,896 eligible invited adults, 5,412 (54·7%) completed surveys; 5,011 (92·6%) respondents met screening criteria and were analysed, including 1,362 (27·2%) caregivers. Caregivers had higher prevalences of adverse mental health symptoms than non-caregivers, including anxiety or depressive disorder symptoms (57·6% vs 21·5%, respectively, pInterpretation: Caregivers, who accounted for one in four US adult respondents in this nationally representative sample, more commonly reported adverse mental health symptoms than non-caregivers. Increased visibility of and access to mental health care resources are urgently needed to address mental health challenges of caregiving.Funding Statement: Monash University; Austin Health; Phillips Respironics; Whoop Inc; Alexandra DraneDeclaration of Interests: All authors report grants from Whoop, Inc., which supported in part administration of the survey in June 2020, and other support from ARCHANGELS, which permitted the investigators to use the proprietary ARCHANGELS Caregiver Intensity Index for this study without cost. Mr Czeisler reports grants from Australian-American Fulbright Commission administered through a 2020 Fulbright Future Scholarship funded by The Kinghorn Foundation, and personal fees from Vanda Pharmaceuticals, outside the submitted work. Ms Drane is co-founder of and employed by ARCHANGELS and receives salary and has equity. Ms Drane reports grants from Ralph C Wilson Junior Foundation; personal fees from Prudential Financial Services and Walmart; and other from RAND Health, Rosalynn Carter Institute for Caregivers, United States of Care - Entrepreneurs Council, Open Notes, Executive Council for Division of Sleep Medicine – Harvard Medical School, Massachusetts Technology Collaborative, C-TAC, EndWell, Beth Israel Deaconess Medical Center, MassChallenge Health Tech, Boston Children's Hospital, Health Evolution, Edenbridge Health, WHOOP, and HPT Development/Drane Associates, outside the submitted work. Ms Stephens Winnay reports a grant from Ralph C Wilson Junior Foundation (RCWJF), outside the submitted work. In addition, Ms Drane and Ms Winnay have a patent ARCHANGELS - Planned pending on the ARCHANGELS Caregiver Intensity Index, and a patent ARCHANGELS CII - Trademark pending on the ARCHANGELS Caregiver Intensity Index. Ms Capodilupo is employed by WHOOP, Inc., from which she receives salary and is a company shareholder, and is on the board of advisors at ARCHANGELS, and is a company shareholder. Dr Czeisler reports institutional education and research support from Cephalon, Inc. and from Philips Respironics Inc.; institutional grants from National Institute of Occupational Safety and Health R01-OH-011773; personal fees from and equity interest in Vanda Pharmaceuticals Inc; personal fees from Teva Pharmaceuticals Industries Ltd, Teva Pharma Australia, outside the submitted work. In addition, Dr Czeisler has a patent for the Actiwatch-2 and Actiwatch-Spectrum devices, with royalties paid from Philips Respironics Inc. Dr Czeisler's interests were reviewed and managed by Brigham and Women's Hospital and Mass General Brigham in accordance with their conflict of interest policies. Dr Czeisler served as a voluntary board member for the Institute for Experimental Psychiatry Research Foundation, Inc. Dr Shantha Rajaratnam reports grants from Turner Institute for Brain and Mental Health, Monash University; grants and personal fees from Cooperative Research Centre for Alertness, Safety and Productivity; grants and institutional consulting fees from Vanda Pharmaceuticals, and Teva Pharmaceuticals; and institutional consulting fees from BHP Billiton, Circadian Therapeutics, and Herbert Smith Freehills, outside the submitted work. Dr Mark Howard reports a grant from the Institute for Breathing and Sleep, Austin Health. No other potential competing interests were declared.Ethics Approval Statement: The Monash University Human Research Ethics Committee reviewed and approved the study protocol on human subjects research (ID #24036). This activity was also reviewed by CDC and was conducted consistent with applicable federal law and CDC policy (45 CFR part 46, 21 CFR part 56; 42 USC Sect 241(d); 5 USC Sect 552a; 44 USC Sect 3501 et seq).