BACKGROUND: Nonpharmaceutical interventions (NPIs) (such as wearing masks and social distancing) have been implemented by governments around the world to slow the spread of COVID-19. To promote public adherence to these regimes, governments need to understand the public perceptions and attitudes toward NPI regimes and the factors that influence them. Twitter data offer a means to capture these insights. OBJECTIVE: The objective of this study is to identify tweets about COVID-19 NPIs in six countries and compare the trends in public perceptions and attitudes toward NPIs across these countries. The aim is to identify factors that influenced public perceptions and attitudes about NPI regimes during the early phases of the COVID-19 pandemic. METHODS: We analyzed 777,869 English language tweets about COVID-19 NPIs in six countries (Australia, Canada, New Zealand, Ireland, the United Kingdom, and the United States). The relationship between tweet frequencies and case numbers was assessed using a Pearson correlation analysis. Topic modeling was used to isolate tweets about NPIs. A comparative analysis of NPIs between countries was conducted. RESULTS: The proportion of NPI-related topics, relative to all topics, varied between countries. The New Zealand data set displayed the greatest attention to NPIs, and the US data set showed the lowest. The relationship between tweet frequencies and case numbers was statistically significant only for Australia (r=0.837, P<.001) and New Zealand (r=0.747, P<.001). Topic modeling produced 131 topics related to one of 22 NPIs, grouped into seven NPI categories: Personal Protection (n=15), Social Distancing (n=9), Testing and Tracing (n=10), Gathering Restrictions (n=18), Lockdown (n=42), Travel Restrictions (n=14), and Workplace Closures (n=23). While less restrictive NPIs gained widespread support, more restrictive NPIs were perceived differently across countries. Four characteristics of these regimes were seen to influence public adherence to NPIs: timeliness of implementation, NPI campaign strategies, inconsistent information, and enforcement strategies. CONCLUSIONS: Twitter offers a means to obtain timely feedback about the public response to COVID-19 NPI regimes. Insights gained from this analysis can support government decision making, implementation, and communication strategies about NPI regimes, as well as encourage further discussion about the management of NPI programs for global health events, such as the COVID-19 pandemic.