Although several quantitative studies have explored vaccine hesitancy, qualitative research on the factors underlying attitudes toward vaccination is still lacking. To fill this gap, this study aimed to investigate the general perceptions of COVID-19 vaccines among the Italian population with a qualitative approach. The sample included 700 Italian participants who completed an online survey. Open questions underwent a descriptive analysis for unveiling meaning categories, while differences in the prevalence of categories were calculated using chi-square or Fisher’s exact tests. Vaccination was associated with the following seven main themes: ‘safety’, ‘healthcare’, ‘vaccine delivery’, ‘progress’, ‘ambivalence’, ‘mistrust’, and ‘ethics’. Vaccinated individuals more frequently reported words related to the safety theme (χ2 = 46.7, p < 0.001), while unvaccinated individuals more frequently reported words related to mistrust (χ2 = 123, p < 0.001) and ambivalence (χ2 = 48.3, p < 0.001) themes. Working in the healthcare sector and being younger than 40 years affected the general perceptions of vaccination in terms of pro-vaccine attitudes. Unvaccinated individuals were more affected by the negative experiences of their acquaintances and manifested more distrust of scientific researchers, doctors, and pharmaceutical companies than vaccinated individuals. These findings suggest promoting collaborative efforts of governments, health policymakers, and media sources, including social media companies, in order to deal with cognitions and emotions supporting vaccine hesitancy.