Emergency medical service (EMS) personnel and firefighters (FFs) are first responders in dangerous and stressful situations. They experience high stress due to the nature of their jobs, which can affect their quality of life and various health dimensions. This study aimed to compare quality of life, job stress, and coping strategies in a sample of EMS personnel and FF employees in Iran. This cross-sectional study included 186 FFs and EMS, who were selected using a census sampling method. Our results showed that FFs had a better quality of life, lower perceived stress, and better coping skills than EMS. Individuals living in rural areas, government officials, and staff with regular work shifts also reported less perceived stress. Furthermore, our results indicated a negative and significant correlation between perceived stress and quality of life and a positive and significant correlation between stress management and quality of life in both groups. Given the inevitability of stress in EMS and FF jobs, policymakers need to take interventional measures to reduce anxiety and enhance the quality of life and work for these personnel. Occupational health policies in Iran generally follow the International Labor Organizational recommended standards, however, more attention to managerial interventions that reduce job demands and job stress combined with health promotion programs to improve coping are advised.