Abstract Introduction We know that patient and caregiver sex influence patient self‐care and caregiver contribution to self‐care in multiple chronic conditions. However, the role of dyad sex combination (e.g., male patient and female caregiver, female patient and male caregiver, male patient and caregiver, and female patient and caregiver) in influencing patient self‐care and caregiver contribution to self‐care remains unexplored. Our aim was to investigate the relationship between patient and caregiver sex combination and patient self‐care and caregiver contribution to self‐care in multiple chronic conditions. Design Multicentre cross‐sectional study. Methods We enrolled patients with multiple chronic conditions and caregiver dyads in outpatient and community settings from April 2017 to December 2019. We used the Self‐Care of Chronic Illness Inventory and the Caregiver Contribution to Self‐Care of Chronic Illness Inventory that measure, from the patient and caregiver perspective, self‐care maintenance (i.e., behaviors to maintain illness stability), self‐care monitoring (i.e., monitoring of illness signs and symptoms), and self‐care management (i.e., behaviors to manage signs and symptoms). We used multivariate analysis of covariance to evaluate the association between sex and self‐care and caregiver contribution to self‐care. Results We recruited 540 patient–caregiver dyads. Male patients cared by female caregivers performed higher self‐care maintenance compared to female patients cared by female caregivers. Female caregivers caring for female patients performed higher caregiver contribution to self‐care monitoring compared to male caregivers caring for female or male patients. Conclusions Clinicians should consider the influence of patient and caregiver sex combination on self‐care and caregiver contribution to self‐care in multiple chronic conditions to provide tailored interventions. Clinical Relevance Healthcare professionals should consider the patient and caregiver sex combination in the dyad to tailor better interventions aimed at improving patient self‐care and caregiver contribution to self‐care in multiple chronic conditions.