This study examines vaccine agreements in South Tyrol, Italy, within distinct socio-cultural and linguistic contexts. Using data from the 2021 and 2023 “COVID-19 Snapshot Monitoring” extended surveys, we assessed changes in attitudes towards COVID-19 and other vaccinations during the second and final years of the pandemic. Multivariate logistic regression analysis was used to examine factors such as trust in institutions, language groups, and the use of complementary and alternative medicine. The representativeness of the study is supported by good participation rates, ensuring a comprehensive view of attitudes towards vaccination in the region. The results show a shift in public agreement with the national vaccination plan to 64% by 2023, from a rate of about 73% agreement in 2021 (p < 0.001). A significant decrease in trust in health authorities and a negative correlation with complementary and alternative medicine consultations were observed. The results highlight the complex nature of vaccine hesitancy in diverse regions such as South Tyrol and underline the need for targeted communication strategies and trust-building initiatives to effectively reduce hesitancy. This study provides critical insights for the formulation of public health strategies in diverse sociocultural settings.