Background: The high burden of chronic communicable diseases such as HIV/AIDS, and an escalating rise of non-communicable diseases (NCDs) in Malawi and other African countries, calls for a shift in how healthcare services are designed and delivered. Patient-centred care and patient self-management are critical elements in chronic care, and advocated as global strategies. Further evidence is needed around patient self-management practices, and how to best support patients with chronic conditions in the African context. Our study explored self-management practices of patients with different chronic conditions, and their strategies to overcome care challenges in a resource constrained setting in Malawi. To further unpack self-management mechanisms and patient adjustment processes, we make use of Bandura’s social cognitive theory. Methods: We conducted a mixed methods study, involving patients with different chronic conditions from a rural district in Malawi. Data included a longitudinal survey with 129 patients, 14 in-depth interviews, and four focus-group discussions with patients. We used a framework approach for qualitative data analysis and survey data analysed using descriptive statistics. Results: Patients demonstrated ability to self-manage their conditions, though this varied between conditions, and was influenced by individual and environmental factors. Factors included: ability to acquire appropriate disease-specific knowledge; poverty level; the presence of support from family caregivers and community-based support initiatives; the nature of one's social relations; and the ability to deal with stressors and stigma. NCD and HIV comorbid patients were more disadvantaged in their access to healthcare, as they experienced frequent drug stock-outs and incurred additional out of pocket costs when referred. These barriers contributed to delayed care, poorer treatment adherence and likelihood of poorer treatment outcomes. Patients proved resourceful and made adjustments in the face of (multiple) care challenges. Discussion and conclusion: We found that patient adaptiveness is an individualised process and relies on how well a patient is able to cope with circumstances in their environment. Bandura’s social cognitive theory further elaborates adaptation as a process where patients develop different mechanisms. For instance, patients create internal models based on successful management of past experiences/events to deal with current challenges (symbolising); or choose to avoid situations that cause distress (self-regulation); or observe and learn complex skills from others such as peers in support groups (vicarious learning). We found evidence of the development of such mechanisms, but it proved difficult to delineate them from the broader patient environment, which was characterised by a heavy reliance on family support and restricted access to resources in their external environment. These in turn influenced patient experiences and strategies for self-management. As Malawi strives towards attaining universal healthcare, affordability and access to NCD services through the public sector presents a formidable challenge, particularly for the rural parts of the country. We recommend introducing peer-patient and support group initiatives for patients with NCDs, and further investments in the decentralisation of integrated health services. Limitation: Our research focused on one rural district in Malawi, hence transferability of our findings to contexts with different characteristics, such as urban setting(s), should be taken into consideration.