Background The rollout of vaccines for COVID-19 in the United Kingdom started in December 2020. Uptake has been high, and there has been a subsequent reduction in infections, hospitalizations, and deaths among vaccinated individuals. However, vaccine hesitancy remains a concern, in particular relating to adverse effects following immunization (AEFIs). Social media analysis has the potential to inform policy makers about AEFIs being discussed by the public as well as public attitudes toward the national immunization campaign.Objective We sought to assess the frequency and nature of AEFI-related mentions on social media in the United Kingdom and to provide insights on public sentiments toward COVID-19 vaccines.Methods We extracted and analyzed over 121,406 relevant Twitter and Facebook posts, from December 8, 2020, to April 30, 2021. These were thematically filtered using a 2-step approach, initially using COVID-19–related keywords and then using vaccine- and manufacturer-related keywords. We identified AEFI-related keywords and modeled their word frequency to monitor their trends over 2-week periods. We also adapted and utilized our recently developed hybrid ensemble model, which combines state-of-the-art lexicon rule–based and deep learning–based approaches, to analyze sentiment trends relating to the main vaccines available in the United Kingdom.Results Our COVID-19 AEFI search strategy identified 46,762 unique Facebook posts by 14,346 users and 74,644 tweets (excluding retweets) by 36,446 users over the 4-month period. We identified an increasing trend in the number of mentions for each AEFI on social media over the study period. The most frequent AEFI mentions were found to be symptoms related to appetite (n=79,132, 14%), allergy (n=53,924, 9%), injection site (n=56,152, 10%), and clots (n=43,907, 8%). We also found some rarely reported AEFIs such as Bell palsy (n=11,909, 2%) and Guillain-Barre syndrome (n=9576, 2%) being discussed as frequently as more well-known side effects like headache (n=10,641, 2%), fever (n=12,707, 2%), and diarrhea (n=16,559, 3%). Overall, we found public sentiment toward vaccines and their manufacturers to be largely positive (58%), with a near equal split between negative (22%) and neutral (19%) sentiments. The sentiment trend was relatively steady over time and had minor variations, likely based on political and regulatory announcements and debates.Conclusions The most frequently discussed COVID-19 AEFIs on social media were found to be broadly consistent with those reported in the literature and by government pharmacovigilance. We also detected potential safety signals from our analysis that have been detected elsewhere and are currently being investigated. As such, we believe our findings support the use of social media analysis to provide a complementary data source to conventional knowledge sources being used for pharmacovigilance purposes.