Background: Healthcare workers were at high risk of contracting COVID-19 during the pandemic due to their frontline commitment. This risk was higher than in the general population because they were exposed to the virus both at work and outside the hospital. Healthcare workers suffered from physical and psychological stress, which could lead to mental health problems. Aims: The aim of the study was to evaluate the effectiveness of four proactive interventions implemented to protect workers' health during the COVID-19 pandemic at the “Federico II” University Hospital in Naples, Italy. The study aimed to prevent both clinical and non-clinical risks, such as infections contagion and work-related stress. Methods: A prospective observational study was conducted between April 9 and May 21, 2020, at the “Federico II” University Hospital. Healthcare personnel, who worked during the study period, were subject to four proactive interventions: (I) Classification based on the risk of exposure to SARS-Cov-2; (II) Healthcare surveillance: diagnostic surveillance (nasopharyngeal swabs for SARS-Cov-2, rapid antigen tests and serological for the detection of IgM/IgG antibodies against SARS-Cov-2), clinical and epidemiological surveillance (physical examination and contact tracing), individual psychological support; (III) Contacts-tracing;(IV) Constant training and information. The study analysed the number of positive swabs in healthcare workers and hospitalised patients during the same period, comparing the incidence of cases with international data. Feedback from psychologists and occupational doctors was also collected to evaluate the impact on non-clinical risks. Results: The study found a low correlation between positive swabs in healthcare workers and patients, suggesting that the preventive measures in place were effective. Furthermore, feedback from psychologists and occupational doctors did not report an increase in stress-related sick leaves, thanks to the proactive actions. Conclusions: The considered proactive interventions proved to be useful to protect healthcare workers during the pandemic. The study highlights the importance of a proactive approach instead of a reactive one, and the necessity to contemplate both the protection from biological risks and the psychological support.