Background <p>Work engagement is vitally crucial in nursing practice. While hindrance-challenge stress significantly influence work engagement across many professions, their specific effects and underlying mechanisms in nursing remain unclear.</p> Aims <p>To investigate how hindrance-challenge stress affect nurses’ work engagement, examining the mediating role of self-regulatory fatigue and the moderating role of self-compassion.</p> Methods <p>A cross-sectional online survey was conducted among 559 nurses in a public tertiary medical center in Nanjing, China. Standardized measures for hindrance-challenge stress, self-regulatory fatigue, work engagement, and self-compassion were employed, and a moderated mediation model was tested via the PROCESS macro in SPSS software (v22.0).</p> Results <p>Hindrance stress reduced work engagement both directly and indirectly via self-regulatory fatigue. Challenge stress influenced work engagement only indirectly through self-regulatory fatigue. Self-compassion moderated the direct effect of hindrance stress, weakening its negative impact on work engagement among nurses with high self-compassion.</p> Conclusions <p>Hindrance and challenge stress diminish nurses’ work engagement through self-regulatory fatigue, with self-compassion mitigating the direct detrimental impact of hindrance stress.</p> Implications for nursing management <p>Nursing leaders can enhance nurses’ work engagement by mitigating hindrance-challenge stress and alleviating self-regulatory fatigue. This may be achieved through improved working conditions, optimized workload allocation, and the provision of robust organizational support resources. Furthermore, fostering self-compassion is essential, as it serves to buffer the detrimental effects of hindrance stress on engagement. Nurse managers are encouraged to implement interventions such as compassion-focused therapy or mindful self-compassion training to help maintain nurses’ engagement in high-demand clinical environments.</p>