Background <p>Self-medication among persons living with HIV/AIDS (PLWHA) is a growing concern in healthcare management, with potential risks including antiretroviral therapy interactions, delayed appropriate treatment, and compromised immune system management. However, limited research exists on the motivations and perceived benefits driving these practices particularly among PLWHA. The study explored self-medication practices, underlying motivations, and perceived benefits among PLWHA in Ghana.</p> Methods <p>A qualitative descriptive study using semi-structured interviews was conducted within July 2024 with 12 PLWHA (9 females, 3 males; aged 23–43 years) purposively sampled from Swedru Municipal Hospital. Data were analyzed using inductive thematic content analysis following Braun and Clarke’s six-step framework. An iterative approach was employed to identify themes, ensuring a thorough representation of PLWHA’ perspectives.</p> Results <p>Three major themes emerged: types of self-medication (conventional pharmaceutical medications including paracetamol, flagyl, ibuprofen, and herbal remedies like neem tree and bitter leaf), motivating factors (accessibility, cost-effectiveness, stigma avoidance, and immediate symptom relief), and perceived benefits (therapeutic efficacy, psychological empowerment, and cultural validation). Participants utilized both conventional pharmaceutical medications and traditional remedies, driven by healthcare access barriers and sociocultural factors. Self-medication served as both a practical healthcare strategy and a means of maintaining autonomy.</p> Conclusions <p>Self-medication among PLWHA reflects complex interactions between healthcare accessibility, cultural practices, and psychological needs. Healthcare systems should develop integrated approaches that balance patient autonomy with medical safety while acknowledging cultural healing practices.</p>