Flu vaccination is recommended among healthcare workers (HCWs). The low vaccination coverage registered in our hospital among HCWs called for new engaging approaches to improve flu vaccination coverage. The aim of this study was to evaluate the efficacy of different strategies implemented during the last four years (2015–2019). A quasi-experimental study was conducted, involving almost 4000 HCWs each year. Starting from the 2015–2016 campaign, new evidence-based strategies were progressively implemented. At the end of each campaign, an evaluation of the vaccination coverage rate reached was performed. Moreover, during the last three campaigns, differences in coverage among job category, wards involved or not in on-site vaccination (OSV) intervention, age classes and gender were analyzed. An increasing flu vaccination coverage rate was registered, from 6% in 2015–2016 to almost 22% at the end of 2018–2019. The overall number of vaccinated HCWs increased, especially at younger ages. OSV strategy always leads to better results, and physicians always show a higher vaccination coverage than nurses and other HCWs. The implemented strategies were effective in achieving higher flu vaccination coverage among HCWs in our hospital and therefore can be considered valuable examples of good prevention practices in hospital settings.