Burnout is attributed to negative work environments and threatens patient and clinician safety. Psychological safety is the perception that the work environment is safe for interpersonal risk-taking and may offer insight into the relationship between the work environment and burnout. In this cross-sectional analysis of survey data from 621 nurse practitioners in California, we found that one-third (34%) experienced high burnout. Four factors in the work environment were negatively associated with burnout and positively associated with psychological safety. Significant mediation effects of psychological safety were observed on the relationships between each work environment factor and both emotional exhaustion and depersonalization. The largest mediation effects were observed on the total effects of Nurse Practitioner-Physician Relations and Practice Visibility on Emotional Exhaustion (37% and 32%, respectively) and Independent Practice and Support and NP-Administration Relations on Depersonalization (32% and 29%, respectively). We found, overall, that psychological safety decreased the strength of the negative relationship between work environment and burnout. We argue that research, practice, and policy efforts to mitigate burnout and improve the work environment should consider psychological safety as a metric for system-level well-being.