Background: The growing population of older adults and the prevalence of multiple chronic conditions (MCCs) among them present significant challenges in care and treatment. Self-management is an effective approach to managing the consequences of MCCs. Objectives: This study aimed to explore the psychosocial and biological factors related to self-management among older adults with MCCs. Methods: This qualitative study employed a content analysis approach from June to April 2023 in hospitals and universities in Tehran. The sample consisted of 26 participants, including older adults with MCCs, family caregivers, and specialists. Data were collected through semi-structured interviews. Purposeful sampling was used, and continued until data saturation was achieved. The rigor of the study was evaluated using the Lincoln and Guba criteria, and analysis was conducted simultaneously with data collection using the Elo and Kyngäs methods. Results: The final analysis identified several factors affecting self-management. A total of 697 semantic units and 336 codes were categorized into 13 subcategories and 4 main categories. These categories included: Individual factors (biological factors, cognitive factors, coexisting diseases, mental health, economic status, health-oriented behaviors), interpersonal factors (interaction with the medical care team, family relationships), factors related to the health system (facilities of medical centers, staff empowerment, health policymaking), and extra-organizational factors (cultural factors, social factors). Conclusions: The findings of this study highlight the factors related to self-management in older adults with MCCs, which can be utilized in the design of self-management programs.