Nurses are at the forefront of our health care delivery system and have been reported to exhibit a high level of burnout. Burnout and stress in trauma nurses at a safety-net hospital can negatively impact patient care. Safety-net hospitals are confronted with unique social, financial, as well as resource problems that can potentially make the work environment frustrating. The purpose of this study was to explore the levels of burnout, stress, and job satisfaction in nurses providing care to trauma patients at a Level I safety-net trauma center. A cross-sectional survey design was used to investigate principal factors including personal and professional demographics, burnout, perceived stress, and job satisfaction. Trauma nurses working at a Level I safety-net trauma center are stressed and exhibited moderate degree of burnout. The extent of emotional exhaustion experienced by the nurses varied with work location and was highest in surgical intensive care unit nurses. The level of job satisfaction in terms of opportunities for promotion differed significantly by race and the health status of the nurses. Satisfaction with coworkers was lowest in those nurses between the ages of 60–69 years. Female nurses were more satisfied with their coworkers than male nurses. In addition, the study revealed that significant relationships exist among perceived stress, burnout, and job satisfaction. Work environment significantly impacts burnout, job satisfaction, and perceived stress experienced by trauma nurses in a safety-net hospital. Nursing administration can make an effort to understand the levels of burnout and strategically improve work environment for trauma nurses in order to minimize stressors leading to attrition and enhance job satisfaction.