Objectives: The nursing profession entails many stressful situations and challenges, such as heavy workload, shift work, emotional demands and professional conflicts. In the light of the results of the research conducted so far, flexible coping has occurred to be highly adaptive, as its association with adaptive struggle with the disease, fewer depressive symptoms and both greater mental well-being and better health have been proven. In connection with the above, the aim of this study was to determine the nature of the relationship between cognitive flexibility and flexibility in coping in nurses, taking into account the moderating role of age of the respondents, seniority and the sense of stress. Material and Methods: The study sample consisted of 280 persons working as nurses (age range: 21–66). The number of women and men reflected their percentage distribution in this profession, as it is highly feminized. The following methods were used in the study: the Cognitive Flexibility Inventory (CFI) by Dennis and Vander Wal, the Perceived Stress Scale (PSS-10) by Cohen et al., the Flexibility in Coping with Stress Questionnaire (FCSQ-14) by Basińska et al., and a self-developed survey. Results: As the obtained research results show, cognitive flexibility in both the Control and Alternatives subscales was a predictor of flexible coping and their subscales. The analysis revealed that the model of the relationship between cognitive flexibility and flexibility in coping was moderated by age, seniority and the sense of stress. Conclusions: Coping skills and flexibility are positively correlated with the psychological adjustment of nurses. Int J Occup Med Environ Health. 2020;33(4):507–21