Objective: To investigate the impact of the COVID-19 pandemic on multiple lifestyle changes among adults in the United States (USA). Methods: We conducted a survey, the Health, Ethnicity, and Pandemic (HEAP) Study, in October 2020 among USA adults. Participants were selected from the United States using 48 sampling strata, including age, race, ethnicity, education, and gender, and were asked to report five lifestyle behaviors (i.e., exercise time, screen time, fast-food meal consumption, alcohol drinking, and cigarette smoking) before and during the COVID-19 pandemic. The associations of sociodemographic factors with each lifestyle change were estimated using weighted multivariable logistic regression models. Results: All 2709 HEAP participants were included in this study. Compared to pre-pandemic, the time spent on exercise decreased (32.06 vs. 38.65 min/day; p < 0.001) and screen time increased (6.79 vs. 5.06 h/day; p < 0.001) during the pandemic. The percentage of individuals who reported consuming fast-food meals ≥3 times/week decreased from 37.7% before the pandemic to 33.3% during the pandemic. The percentage of heavy drinkers (≥5 times/week) increased from 20.9% before the pandemic to 25.7% during the pandemic. Among smokers, heavy smoking (≥11 cigarettes/day) increased from 5.8% before the pandemic to 7.9% during the pandemic. We also identified subgroups who were more vulnerable to adverse influences from the pandemic, including racial/ethnic minority groups and young adults. Conclusions: The COVID-19 pandemic had negative impacts on multiple lifestyle behaviors among Americans. Mitigating such negative impacts of COVID-19 requires effective interventions, particularly for some vulnerable subgroups.