BackgroundA growing body of evidence suggests that the COVID‐19 pandemic is adversely impacting the mental health and well‐being of frontline nurses worldwide. It is therefore important to understand how such impact can be mitigated, including by studying psychological capacities that could help the nurses regulate and minimize the impact.AimTo examine the role of psychological flexibility in mitigating the adverse impacts of burnout and low job satisfaction on mental health problems (i.e., anxiety, depression, and stress) and well‐being among the frontline nurses in Hong Kong and Switzerland during the COVID‐19 pandemic.DesignCross‐sectional, two‐region survey study.MethodFour hundred fifty‐two nurses from Hong Kong (n = 158) and Switzerland (n = 294) completed an online survey. An adjusted structured equation model was used to examine the interrelationship of the constructs.ResultsPsychological flexibility was found to partially mediate the effects of job satisfaction on mental well‐being (β = 0.32, 95% CI [0.19, 0.57], p = 0.001) and mental health problems (β = −0.79, 95% CI [−1.57, −0.44], p = 0.001), respectively. Similarly, this partial mediation was found in the effects of burnout on mental well‐being (β = −0.35, 95% CI [−0.89, −0.15], p = 0.002) and mental health problems (β = 0.89, 95% CI [0.48, 3.65], p = 0.001).ConclusionPsychological flexibility could be a crucial psychological resilience factor against the adverse impact of nurses' burnout on their mental health problems and well‐being during COVID‐19.Clinical RelevanceOrganizational measures should focus on fostering psychological flexibility in nurses through highly accessible, brief psychotherapeutic interventions, such as Acceptance and Commitment Therapy, to reduce the impact on mental health.