This study focused on vaccine hesitancy and decision regret about the COVID-19 vaccine among nursing students (BScN and MScN) and Registered Nurses (RNs) in Italy. The primary aim was to describe decision regret and vaccine hesitancy among these groups and to understand what influences vaccine hesitancy. Data were collected through an e-survey conducted from March to June 2024. The Decision Regret Scale and the Adult Vaccine Hesitancy Scale were employed to assess regret and hesitancy levels, assessing trust, concerns, and compliance regarding vaccination. Among the participants, 8.64% were not vaccinated. The results indicated moderate to high levels of decision regret and diverse levels of trust, concerns, and compliance with COVID-19 vaccination. Structural equation modeling revealed that decision regret significantly predicted Trust (R2 = 31.3%) and Concerns (R2 = 26.9%), with lower regret associated with higher trust and lower concerns about vaccine safety. The number of COVID-19 vaccine boosters was a significant predictor of Trust and Concerns, with more boosters associated with higher trust and lower concerns. MScN students exhibited higher Compliance compared to RNs (R2 = 2.9%), highlighting the role of advanced education. These findings suggest that addressing decision regret and providing comprehensive vaccine information could enhance trust and compliance.