Lymphatic filariasis (LF) causes disfiguring and disabling lymphoedema, which can lead to mental distress and requires life-long self-care treatment. This study applies syndemic theory to understand the biosocial relationship between LF and mental distress in Malawi. Using in-depth qualitative methods, we critically evaluate experiences of mental distress and LF through 21 life-history interviews, to narrate experiences from the perspective of persons affected by LF, and to understand how enhanced self-care (ESC) for lymphoedema management disrupts the syndemic relationship. Complementary key informant interviews with Ministry of Health LF programme staff were conducted to further understand intervention and health system delivery. All interviews were recorded, transcribed, and translated, and then subject to thematic analysis. Our findings suggest that for persons affected by LF in Malawi, before being trained in ESC, absent referral pathways, inequalities in healthcare provision or available treatment, and limited knowledge of the condition (LF) drove the syndemic of LF and mental distress. Distress was often exacerbated by stigma and social exclusion, and shaped by intersections of gender, generation, poverty, and extreme climate conditions. We argue that addressing the syndemic suffering associated with LF and mental distress through interventions which center the needs of persons affected is critical in effective and equitable LF care delivery.