Background: Unpaid caregivers of 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 caregiving needs, forcing some into caregiving roles and disrupting others. Objectives: We sought to estimate the prevalence of and identify factors associated with adverse mental health symptoms, substance use, and suicidal ideation amongst unpaid caregivers of adults versus non-caregivers. Methods: During June 24-30, 2020, surveys were administered to U.S. adults. Quota sampling and survey weighting were implemented to improve sample representativeness of age, gender, and race/ethnicity. Results: Of 9,896 eligible invited adults, 5,412 (54.7%) completed surveys and 5,011 (92.6%) met screening criteria and were analyzed, including 1,362 (27.2%) caregivers. Caregivers had higher adverse mental health symptom prevalences than non-caregivers, including suicidal ideation (33.4% vs 3.7%, p < 0.0001). Symptoms were more common among caregivers who were young vs older adults (e.g., aged 18–24 vs ≥65 years, aPR 2.75, 95% CI 1.95–3.88, p < 0.0001) and with moderate and high vs low Caregiver Intensity Index scores (2.31, 1.65–3.23; 2.81, 2.00–3.94; both p < 0.0001). Limitations: Self-report data may be subject to recall, response, and social desirability biases; unpaid caregivers were self-identified; child caregiving roles were not assessed; and internet-based survey samples might not fully represent the U.S. population. Conclusions: Caregivers experienced disproportionately high levels of adverse mental health symptoms. Younger caregivers and those with higher caregiving intensity were disproportionately affected. Increased visibility of and access to mental health care resources are urgently needed to address mental health challenges of caregiving.