Objective Studies on informal caregiving for older persons in Ghana have only reported the challenges of the caregivers without providing their coping mechanisms. Considering the myriad of challenges facing informal caregivers in Ghana, we sought to explore the coping mechanisms utilised by informal caregivers in rural and urban settings of Ghana to overcome their caregiving challenges. Methods In-depth interviews were conducted with 20 purposively selected caregivers from the Ejisu-Juaben Municipality and Kumasi Metropolis in the Ashanti Region of Ghana. The data were thematically analysed and common themes were reported as findings. Results Six key coping mechanisms were found; faith in God, support from friends and family, borrowing from friends, acceptance and encouragement, reducing expenditure on other activities, and taking time off. Conclusion The findings provide key strategies to policy-makers in the health sector to prevent the burnout of informal caregivers. Considerations from the coping mechanisms enumerated in the current study could guide the design and implementation of policies towards improving the informal healthcare sector in Ghana, which is crucial to the realisation of the United Nations' health-related Sustainable Development Goals.