In South Africa, Mental Health (MH), HIV, and Intimate Partner Violence (IPV) form a syndemic, that disproportionately affects women. These challenges are often co-occurring and create complex adversities for women. Recognising these intersections and the broader socio-cultural dynamics at play is crucial to understanding the layered experiences of these women and developing effective interventions. This research explores the experiences of the women living with at least two of the epidemics (HIV, IPV and or MH) and how they cope. A qualitative study design was used and 20 women (22–60 years) were recruited from Mpumalanga, South Africa. To be eligible for the study the women had to have experienced at least two of the epidemics. Data were collected through home-based interviews, arts-based activities, and analysed thematically using MAXQDA (2022) software. MH challenges were prevalent among all the participants and were linked to both IPV and HIV, resulting in symptoms such as anxiety, depression, and suicidal thoughts. In relation to the HIV-MH link, MH challenges in this combination included feelings of denial, sadness and anxiety related to participant’s HIV diagnosis. A bidirectional relationship also existed in the IPV-MH group where pre-existing MH challenges among women increased their vulnerability of having violent partners, whilst IPV also increased MH challenges. In the IPV-MH-HIV group early childhood violence exposure was linked with MH challenges and later victimization and vulnerability to HIV. Participants primarily used religion, acceptance, occasional alcohol, and family support as coping strategies. Particularly in IPV situations, alcohol use/misuse was the most prevalent coping strategies. The study highlights the syndemic relationship between HIV, IPV and MH challenges among South African women living in a peri-urban community, with a central emphasis on MH challenges. Interventions should holistically address these challenges, with particular focus on MH challenges, cultural sensitivity, and promotion of healthy coping strategies.