Aim <p>To assess how work–family conflict relates to depression, burnout, and ICU nurses’ perceptions of patient safety culture in Saudi Arabia.</p> Design <p>A cross-sectional, correlational study.</p> Methods <p>A total of 276 ICU nurses from four tertiary hospitals in the Western Region of Saudi Arabia completed standardized instruments assessing depression (BDI-II), burnout (MBI-HSS), work–family conflict (Carlson et al.), and selected items from the Hospital Survey on Patient Safety Culture (HSOPSC) between May and August 2021. Data were analyzed using descriptive and inferential statistics, including correlation analysis and group comparisons using t-tests and ANOVA.</p> Results <p>High levels of psychological distress were identified: 28% of nurses reported moderate to severe depression, 24% reported high emotional exhaustion, and 89% experienced moderate to high work–family conflict. Depression was significantly correlated with burnout (ρ = 0.522, <i>p</i> &lt; .001) and work–family conflict (ρ = 0.397, <i>p</i> &lt; .001). Safety culture perceptions were fragmented, with low levels of error reporting and communication openness. Less experienced nurses showed higher depression levels.</p> Conclusion <p>ICU nurses in Saudi Arabia experience considerable mental health challenges that may compromise patient safety perceptions. Work–family conflict emerged as a key stressor linked to both depression and burnout.</p> Impact <p>These findings highlight an urgent need for system-level interventions to support nurses’ well-being and psychological safety in ICU settings. Accordingly, mental health services and support programs should be integrated into ICU practice.</p> Patient or public contribution <p>As this was a workforce study there was no patient or public contribution.</p> Clinical trial registration <p>Not applicable. This study is not a clinical trial.</p>