Background Palliative and end-of-life care (PEoLC) played a critical role in relieving distress and providing grief support in response to the heavy toll caused by the COVID-19 pandemic. However, little is known about public opinions concerning PEoLC during the pandemic. Given that social media have the potential to collect real-time public opinions, an analysis of this evidence is vital to guide future policy-making. Objective This study aimed to use social media data to investigate real-time public opinions regarding PEoLC during the COVID-19 crisis and explore the impact of vaccination programs on public opinions about PEoLC. Methods This Twitter-based study explored tweets across 3 English-speaking countries: the United States, the United Kingdom, and Canada. From October 2020 to March 2021, a total of 7951 PEoLC-related tweets with geographic tags were retrieved and identified from a large-scale COVID-19 Twitter data set through the Twitter application programming interface. Topic modeling realized through a pointwise mutual information–based co-occurrence network and Louvain modularity was used to examine latent topics across the 3 countries and across 2 time periods (pre- and postvaccination program periods). Results Commonalities and regional differences among PEoLC topics in the United States, the United Kingdom, and Canada were identified specifically: cancer care and care facilities were of common interest to the public across the 3 countries during the pandemic; the public expressed positive attitudes toward the COVID-19 vaccine and highlighted the protection it affords to PEoLC professionals; and although Twitter users shared their personal experiences about PEoLC in the web-based community during the pandemic, this was more prominent in the United States and Canada. The implementation of the vaccination programs raised the profile of the vaccine discussion; however, this did not influence public opinions about PEoLC. Conclusions Public opinions on Twitter reflected a need for enhanced PEoLC services during the COVID-19 pandemic. The insignificant impact of the vaccination program on public discussion on social media indicated that public concerns regarding PEoLC continued to persist even after the vaccination efforts. Insights gleaned from public opinions regarding PEoLC could provide some clues for policy makers on how to ensure high-quality PEoLC during public health emergencies. In this post–COVID-19 era, PEoLC professionals may wish to continue to examine social media and learn from web-based public discussion how to ease the long-lasting trauma caused by this crisis and prepare for public health emergencies in the future. Besides, our results showed social media’s potential in acting as an effective tool to reflect public opinions in the context of PEoLC.