Background HIV and mental illness comorbidity remain one of the healthcare challenges with limited information and medical care attention. The co-existence of the two, result in poor coping thereby increasing vulnerability and poor health-related wellbeing. A number of strategies for coping with HIV and mental illness have been reported for individual states of HIV and mental illness but there is limited data on comorbidity states. In this study, we aimed at exploring coping strategies for HIV and Mental illness comorbidity among adult patients in southwestern Uganda and potential points of intervention that can mitigate challenges they encounter. Methods A descriptive cross-sectional qualitative study design was used. Purposive sampling was used to recruit 26 adult (≥ 18 years) patients attending health care services at one hospital and one health Centre IV in Sheema and Isingiro district respectively, in southwestern Uganda. Data was collected using in-depth interviews, was audio recorded, transcribed verbatim from the local language and translated into English. Data was managed and analyzed using ATLAS.Ti software. Results A wide range of coping strategies categorized as individual centered, family support, healthcare and social support were reported. Avoidance of emotional stressors like quarrels, worries and annoyance was the most common. Other strategies were; seeking medical care, abstinence from sex, attending educational trainings, health status disclosure and caring for self. In coping with the comorbidity, several challenges were encountered, but various points of intervention including financial aid and scaling up training or educating masses on the causes, dangers and preventive measures of these diseases were suggested to improve the quality of life and also to prevent new infections. Conclusions We found variability in coping strategies categorized as individual centered, family support, healthcare support and social support. Avoidance of emotion stressors was a common coping strategy among the respondents. Several challenges are encountered in coping but potential points of interventions to mitigate the challenges were identified. Scaling up healthcare education for all, and tailored trainings to promote coping with HIV and mental illness comorbidity, together with adopting financial aid programs directed towards poverty alleviation among these patients were recommended.