The outbreak of the COVID-19 pandemic posed an immediate challenge to the management of hospitals in Germany and elsewhere. The risk of stress for front-line healthcare professionals forced occupational health and safety units to adopt a variety of protective measures, not all of which have been thoroughly validated. The main objective of the present analysis is to assess what the most important sources of stress were and which of the protective measures applied to counteract stress among healthcare staff had the greatest impact. A better understanding of these factors will improve hospital management and worker safety in a future health crisis situation and may also prove to be beneficial in non-crisis situations. For this purpose, in 2020, an exploratory, cross-sectional and quantitative study using a questionnaire created for this purpose was carried out on a total of 198 professionals—133 nurses and 65 physicians—at the Klinikum Mittelbaden Balg hospital in Baden-Baden, Germany, during the first wave of the pandemic. Statistical analyses showed that nurses suffer more stress than physicians and that stress is higher among professionals in critical care and emergency units than in units that are less exposed to infected patients. It was also found that measures such as salary incentives, encouragement of work in well-integrated teams, and perceived support from hospital management mitigate stress. These findings highlight the importance of support measures from management and superiors. Knowing the actual effectiveness of the measures applied by management and the factors mentioned above could help to protect healthcare professionals in the event of another pandemic or similar situations and may still be of value in dealing with the continuing COVID-19 pandemic.