Political and public health leaders promoting COVID-19 vaccination should identify the most relevant criteria driving the vaccination decision. Social media is increasingly used as a source of vaccination data and as a powerful communication tool to increase vaccination. In December 2020, we performed a cross-sectional social media-based survey addressing personal sentiments toward COVID-19 vaccination in the USA. Our primary research objective is to identify socio-demographic characteristics and the reasons for the 1644 survey participants’ attitudes regarding vaccination. We present clear evidence that, contrary to the prevailing public perceptions, young audiences using social media have mostly a positive attitude towards COVID-19 vaccination (81.5%). These younger individuals want to protect their families and their relatives (96.7%); they see vaccination as an act of civic responsibility (91.9%) and express strong confidence in their healthcare providers (87.7%). Another critical factor is the younger population’s fear of personal COVID-19 infection (88.2%); moreover, the greater the number of children the participants have, the greater is their intent to get the COVID-19 vaccine. These results enable a practical public-messaging pathway to reinforce vaccination campaigns addressing the younger population.