Background This study contributes to a small but growing body of literature on how context influences perceptions of patient safety in healthcare settings. We examine the impact of senior leadership support for safety, supervisory leadership support for safety, teamwork, and turnover intention on overall patient safety grade. Interaction effects of predictors on perceptions of patient safety are also examined.Methods Cross-sectional survey data (N = 185) were collected from nurses and non-physician healthcare professionals. Semi-structured interview data (N = 15) were collected from nurses. The study participants worked in intensive care, general medicine, mental health, or the emergency department of a large community hospital in Southern Ontario.Results Hierarchical regression analyses showed that staff perceptions of senior leadership (p < 0.001), teamwork (p < 0.01), and turnover intention (p < 0.01) were significantly associated with overall patient safety grade. The interactive effect of teamwork and turnover intention on overall patient safety grade was also found to be significant (p < 0.05). The qualitative findings corroborated the survey results but also helped expand the characteristics of the study’s key concepts (e.g., teamwork within and across professional boundaries) and why certain statistical relationships were found to be non-significant (e.g., nurse interviewees perceived the safety specific responsibilities of frontline supervisors much more broadly compared to the narrower conceptualization of the construct in the survey).Conclusions The results of the current study suggest that senior leadership, teamwork, and turnover intention significantly impact nursing staff perceptions of patient safety. Leadership is a modifiable contextual factor and resources should be dedicated to strengthen relational competencies of healthcare leaders. Healthcare organizations must also proactively foster inter and intra-professional collaboration by providing teamwork educational workshops or other on-site learning opportunities (e.g., simulation training). Healthcare organizations would benefit by considering the interactive effect of contextual factors as another lever for patient safety improvement, e.g., lowering staff turnover intentions would maximize the positive impact of teamwork improvement initiatives on patient safety.