Addressing gaps in COVID-19 vaccine-hesitancy research, the current study aimed to add depth and nuance to the exploratory research examining vaccine-hesitant groups. Using a larger, but more focused conversation occurring on social media, the results can be used by health communicators to frame emotionally resonant messaging to improve COVID-19 vaccine advocacy while also mitigating negative concerns for vaccine-hesitant individuals. Social media mentions were collected using a social media listening software, Brandwatch, to examine topics and sentiments in COVID-19 hesitancy discourse during a period of September 1, 2020, through December 31, 2020. The results from this query included publicly available mentions on two popular social media sites, Twitter and Reddit. The dataset of 14,901 global, English language messages were analyzed using a computer-assisted process in SAS text-mining and Brandwatch software. The data revealed eight unique topics before being analyzed by sentiment. Among the COVID-19 hesitancy data, trust-related topics emerged that included declining vaccine acceptance, a parallel pandemic of distrust, and a call for politicians to let the scientific process work, among others. Positive sentiment revealed interest in the sources which included healthcare professionals, doctors, and government organizations. Pfizer was found to elicit both positive and negative emotions in the vaccine-hesitancy data. The negative sentiment tended to dominate the hesitancy conversation, accelerating once vaccines hit the market. Relevant topics were identified to help support targeted communication, strategically accelerate vaccine acceptance, and mitigate COVID-19 vaccine hesitancy among the public. Strategic methods of online and offline messaging tactics are suggested to reach diverse, malleable populations of interest. Topics of personal anecdotes of safety, effectiveness, and recommendations among families are identified as persuasive communication opportunities.