The rapid development of the vaccine and the infodemia have challenged communication about COVID-19 vaccines. This study aims to characterize—through the experience of vaccinators—the challenges faced during COVID-19 vaccination consultations and the communication strategies adopted. A qualitative study was conducted on COVID-19 vaccinators in Tuscany, Italy. Face-to-face interviews were conducted and examined by thematic analysis. In total, 30 vaccinators were interviewed. Four main themes emerged. The first highlighted distinct profiles of users’ attitudes toward COVID-19 vaccination. Barriers and promoters of vaccine uptake emerged in the second theme: concerns over the vaccine, excessive exposure to information, and a lack of clear guidance from institutions were the main factors behind hesitancy. The third theme highlighted users’ information-seeking behaviors; vaccinators observed that users ideologically opposed to the vaccine (IOV) unconsciously seek information that confirms their theories. The last theme comprised communication strategies for dealing with hesitancy. Empathy, first-hand examples, transparency, and tailored communication style appear to be effective in building vaccine trust. Lastly, the impossibility of developing a decision-making partnership with IOVs was noticed. These findings may help to better characterize public attitudes toward COVID-19 vaccination and highlight key communication principles and strategies to foster vaccine confidence.