Introduction Around one-third of Americans reported they were unwilling to get a COVID-19 vaccine in April 2021. This focus group study aimed to provide insights on the factors contributing to unvaccinated adults’ hesitancy or refusal to get vaccinated with COVID-19 vaccines. Method Ipsos recruited 59 unvaccinated US adults who were vaccine hesitant (i.e., conflicted about or opposed to receiving a COVID-19 vaccination) using the Ipsos KnowledgePanel. Trained facilitators led a total of 10 focus groups via video-conference in March and April 2021. Two coders manually coded the data from each group using a coding frame based on the focus group discussion guide. The coding team collaborated in analyzing the data for key themes. Results Data analysis of transcripts from the focus groups illuminated four main themes associated with COVID-19 vaccine hesitancy: lack of trust in experts and institutions; concern about the safety of COVID-19 vaccines; resistance towards prescriptive guidance and restrictions; and, despite personal reluctance or unwillingness to get vaccinated, acceptance of others getting vaccinated. Discussion Vaccine confidence communication strategies should address individual concerns, describe the benefits of COVID-19 vaccination, and highlight evolving science using factural and neutral presentations of information to foster trust.