BACKGROUND/AIM: Understanding the social context of e-cigarette use in the United States (U.S.) remains a high priority. METHODS: In this cross-sectional study, we included 68,356 adults aged ≥18 from the All of Us research program's COVID-19 Participant Experience (COPE) survey who had complete e-cigarette use information. Multivariable-adjusted logistic regression was used to examine the association between e-cigarette use (current, former, and never), psychological distress, and substance use. RESULTS: In the sample, most were male (66.3 %) and white (81.9 %), with 2.9 % reporting former and 2.3 % current e-cigarette use. Individuals reporting former or current e-cigarette use had a higher prevalence of psychological distress (e.g., depressive symptoms: never 49.6 %, former 70.2 %, current 73.4 %) and substance use (e.g., cannabis: never 9.8 %, former 37.0 %, current 42.6 %) than never e-cigarette use. Compared with never use, current e-cigarette use was associated with higher odds of depressive symptoms (aOR, 1.53 95 % CI: 1.34-1.74), anxiety (aOR1.36, 1.19-1.57), suicidal ideation (aOR1.55, 1.32-1.82), stress (aOR1.41, 1.24-1.59), as well as, cannabis (aOR 2.72, 2.40-3.08), opioids (aOR1.92, 1.56-2.36), stimulants (aOR2.33, 1.91-2.83), sedatives (aOR1.68, 1.43-1.98), hallucinogens (aOR1.94, 1.28-2.90), and cocaine use (aOR1.85, 1.21-2.79). Similar significant associations were observed in former, occasional and daily e-cigarette use, with comparable estimates across sexes. CONCLUSION: In this unique well-powered All of US dataset, there was a significant cross-sectional association between e-cigarette use, psychological distress, and substance use, indicating that the social context of e-cigarette use is closely linked to key well-being domains. These data provide high precision estimates that can be used to inform interventions aimed at creating awareness of e-cigarette use correlates.