Background: High rates of mental distress, mental illness, and the associated physical effects of psychological injury experienced by ambulance personnel has been widely reported in quantitative research. However, there is limited understanding of how the nature of ambulance work contributes to this problem, the significant large toll that emergency medical response takes on the individual, and particularly about late and cumulative development of work-related distress among this first responder workforce. Methods: This study examined peer-reviewed qualitative research published from 2000 to 2018 to outline the effect of emergency medical response work on the psychological, psychosocial, and physical health of paramedics, ambulance officers, ambulance volunteers, and call-takers. Databases searched included: Ovid Medline, CINAHL, Ovid EMcare, PsychInfo and Scopus. The systematic review was organised around five key areas: impact of the work on psychological wellbeing; impact of psychological stress on physical wellbeing; how work-related well-being needs were articulated; effects of workflow and the nature of the work on well-being; and, effects of organisational structures on psychological and physical well-being. Results: Thirty-nine articles met the eligibility criteria. Several factors present in the day-to-day work of ambulance personnel, and in how organisational management acknowledge and respond, were identified as being significant and contributing to mental health and well-being, or increasing the risk for developing conditions such as PTSD, depression, and anxiety. Ambulance personnel articulated their well-being needs across four key areas: organisational support; informal support; use of humour; and individual mechanisms to cope such as detachment and external supports. Conclusions: Interactions between critical incidents and workplace culture and demands have an overwhelming impact on the psychological, physical and social well-being of ambulance personnel. These include day-to-day managerial actions and responses, the impact of shift work, poorly-managed rosters, and long hours of work with little time between for recovery. Mental health issues result from exposure to traumatic events, and the way managers and peers respond to worker distress. Ambulance personnel suffering from work-related stress feel abandoned by peers, management, and the service, during illness, in return-to-work, and post-retirement. Policy, programmes and interventions, and education need to occur at an individual, peer, organisational, and government level.