This study examined the associations among the cognitive fusion, sense of coherence, rumination, and psychological distress, in cancer patients, as well as the mediating role of emotional dysregulation, in the relationship between this variables in cancer patients. Participants included 200 cancer patients who completed the DASS-21, Cognitive fusion questionnaire, sense of coherence scale, Rumination scale and the DERS-16. Structural equation modeling revealed was a direct associated between rumination with emotion dysregulation and emotion dysregulation with psychological distress. Also, the results indicated that no significant relationship between cognitive fusion and sense of coherence with psychological distress. Interaction-mediation analysis demonstrated that emotion dysregulation in the relationship between cognitive fusion and sense of coherence with psychological distress plays a full mediating role and in the relationship between rumination and psychological distress has minor mediating role. Therefore, considering the relationships between the studied variables and identifying the role of emotional dysregulation as a mediating variable in this regard, paying attention to the findings can be the first step in identifying the variables involved in psychological distress in cancer patients. This is followed by the design and application of evidence-based training and rehabilitation programs to reduce psychological pain and suffering in cancer patients, which can be considered by the mental health team of these patients.