The livelihoods of persons living with HIV/AIDS (PLWHAs) in Ghana and sub-Saharan Africa have generally been under-researched using the social context approach. Employing the social context explanatory framework, we explore the livelihoods and challenges facing 38 PLWHAs in the Lower Manya Krobo Municipality (LMKM) in the Eastern Region of Ghana. LMKM has the highest prevalence of HIV/AIDS in Ghana. In-depth interviews have been conducted with participants who are outpatients at either of the two HIV/AIDS clinics in the study area. Their family relations, healthcare, healthcare seeking, and health status have been explored. The findings show the participants to generally be poor, have poorer health, and to have had some challenges to healthcare seeking, including food insecurity. They also lack sufficient support from family and romantic partners. Most have family members and romantic partners who had succumbed to HIV/AIDS. The participants generally have a high burden of child dependents, including orphans from HIV/AIDS. Our explanatory model confirms that the participants are caught at the interphase of intrapersonal, interpersonal, community, and national vulnerabilities that are interdependent and reciprocal. Safety-net provisions such as the National Health Insurance scheme provide them with inadequate social protection. For improved health status and general livelihood, we recommend more pro-active social support for the participants and their dependents. Furthermore having stakeholders make greater efforts is recommended for strengthening Ghana's economy against shocks.