Introduction: Burn out syndrome and depression often occur in social professions and health professions. As far as nursing staff are concerned, research shows that there is an increased risk of physical and mental health being affected by occupational exposure and depression. Aim: The aim of the present research was to explore of burnout syndrome and depression in nursing staff of the General Hospital of Rhodes. Methods: The data were collected from a sample of 150 nurses who work in General Hospital of Rhodes. The nursing staff was asked to complete an anonymous questionnaire consisting of the questionnaire MBI (Maslach Burnout Inventory) to assess the burnout and the PHQ-9 (Patient Health Questionnaire -9) to assess the depression. Data analysis was contacted by the statistical package SPSS 24. Results: Moderate to high levels were observed for the three dimensions of burnout in nursing staff. Many demographic, individual and work factors are positively related and affect the incidence of occupational burnout and depression in nursing staff. All three components of occupational burnout have been found to be related to "age". Depersonalization was statistically significant with the variable ‘salary’ (p=0.037) and the variable ‘working conditions’, while personal achievements with the variable ‘sex’ (p =0.05) and the variable ‘education’ (p=0.016). 83 nurses (80.6%) experienced depression in the mild form of it (39.8%). A strong positive association was observed between depression and emotional exhaustion with r = 0.7 and sig = 0.01. Conclusions: Early identification and identification of factors affecting the occurrence of burnout and depression is deemed necessary where the health effects of nurses are prevented through intervention by health care managers and appropriate preventive measures.