Purpose <p>This study aimed to examine the relationships between illness perception, cognitive emotion regulation strategies (CERS), and psychological distress, and the mediating role of CERS in breast cancer patients and their spouses.</p> Methods <p>A cross-sectional study recruited 305 pairs of breast cancer patients and their spouses to complete the sociodemographic and clinical characteristics questionnaire, the Cognitive Emotion Regulation Questionnaire-short, and the Hospital Anxiety and Depression Scale. Descriptive statistics, difference analysis, Pearson’s correlation coefficient, and the actor–partner interdependence mediation model were conducted.</p> Results <p>There was a significant correlation between illness perception, CERS, and psychological distress in breast cancer patients and their spouses (<i>r</i> = -0.416 ~ 0.522, <i>P</i> &lt; 0.05). Both patients’ and spouses’ illness perception could directly produce significant actor effects on psychological distress, or indirectly through the mediator of maladaptive or adaptive CERS of their own. Only spouses’ illness perception could produce significant partner effect on patients’ psychological distress. Moreover, only spouses’ illness perception could produce significant effects on patients’ psychological distress through patients’ or spouses’ maladaptive CERS.</p> Conclusion <p>Our findings offered a new perspective on how illness perception, CERS, and psychological distress were interconnected at both personal and dyadic levels. The findings underscored the significance of intervening with breast cancer patients and spouses as a closely knit dyad to promote the adoption of adaptive CERS while reduce the use of maladaptive CERS, which may be associated with lower levels of psychological distress.</p>