As the coronavirus disease 2019 (COVID-19) vaccine is introduced, it is critical to recognize that public opinion on vaccines is largely influenced by health communications, with YouTube being a major source of information and misinformation. This analysis graded the accuracy, quality, and reliability of the most viewed YouTube videos depicting COVID-19 and vaccinations over a 6-mo period. We collected hyperlinks for the 150 most viewed YouTube videos discussing COVID-19 from January through June 2020. Closed captioning data were searched for the term "vaccine," yielding 32 videos. This sample was evaluated for quality, accuracy, and reliability using a rubric that incorporated existing instruments: Global Quality Scale (GQS), JAMA Benchmark Criteria, and DISCERN. These 32 videos had 139,764,188 views at the time of data collection. The majority of videos received low scores, with network news sources receiving the lowest scores overall. The overall quality of COVID-19 YouTube videos related to vaccines may be low and raises a precautionary alert for the public consuming these videos and for health-care providers working to provide the best information to their patients. Existing scoring tools may not capture the complexities of social media. New tools could allow for a better understanding of the modern landscape of health communications.