Background Health behavior is influenced by culture and social context. However, there are limited data evaluating the scope of these influences on COVID-19 response. Objective This study aimed to compare handwashing and social distancing practices in different countries and evaluate practice predictors using the health belief model (HBM). Methods From April 11 to May 1, 2020, we conducted an online, cross-sectional survey disseminated internationally via social media. Participants were adults aged 18 years or older from four different countries: the United States, Mexico, Hong Kong (China), and Taiwan. Primary outcomes were self-reported handwashing and social distancing practices during COVID-19. Predictors included constructs of the HBM: perceived susceptibility, perceived severity, perceived benefits, perceived barriers, self-efficacy, and cues to action. Associations of these constructs with behavioral outcomes were assessed by multivariable logistic regression. Results We analyzed a total of 71,851 participants, with 3070 from the United States, 3946 from Mexico, 1201 from Hong Kong (China), and 63,634 from Taiwan. Of these countries, respondents from the United States adhered to the most social distancing practices (χ23=2169.7, P <.001), while respondents from Taiwan performed the most handwashing (χ23=309.8, P <.001). Multivariable logistic regression analyses indicated that self-efficacy was a positive predictor for handwashing (odds ratio [OR]United States 1.58, 95% CI 1.21-2.07; ORMexico 1.5, 95% CI 1.21-1.96; ORHong Kong 2.48, 95% CI 1.80-3.44; ORTaiwan 2.30, 95% CI 2.21-2.39) and social distancing practices (ORUnited States 1.77, 95% CI 1.24-2.49; ORMexico 1.77, 95% CI 1.40-2.25; ORHong Kong 3.25, 95% CI 2.32-4.62; ORTaiwan 2.58, 95% CI 2.47-2.68) in all countries. Handwashing was positively associated with perceived susceptibility in Mexico, Hong Kong, and Taiwan, while social distancing was positively associated with perceived severity in the United States, Mexico, and Taiwan. Conclusions Social media recruitment strategies can be used to reach a large audience during a pandemic. Self-efficacy was the strongest predictor for handwashing and social distancing. Policies that address relevant health beliefs can facilitate adoption of necessary actions for preventing COVID-19. Our findings may be explained by the timing of government policies, the number of cases reported in each country, individual beliefs, and cultural context.