Antiretroviral therapy (ART) regimens in African countries, including Ghana, are often faced with the challenge of treatment default. To maximize ART utilization and efficiency among people living with HIV (PLHIV), it is pertinent to ensure that ART-related challenges that clients encounter are identified and addressed holistically. A phenomenological qualitative study, consisting of thirty participants recruited through the purposive sampling technique, was conducted using in-depth interviews from June to July 2021. Independent coding was done using Atlas ti. Sub-themes were developed from the codes, using the most expressive phrases, and grouped under two broad themes, challenges, and opportunities to maximize ART uptake. Ten different challenges, grouped into the health system and individual constraints were reported. Health system constraints included stigmatization and discrimination by healthcare workers, queuing outside while waiting to be served, long waiting periods, non-communication of laboratory test results to clients, lack of proper education on side effects associated with ART, and language barrier. Individual constraints included financial constraints, perceived non-improvement in health outcomes, food insecurity, and forgetfulness. Opportunities identified for improved ART uptake were assuring ART clients of ultimate improved health outcomes, leveraging the good rapport between ART clients and healthcare providers, leveraging the better counselling services offered to PLHIV at the ART clinic, provision of varied ART treatment regimens to clients, routine communication of laboratory test results to clients, and leveraging clients’ satisfaction with ART services at ART clinic. We recommend health system reforms targeting healthcare service delivery to PLHIV to encourage linkage, continuity, and retention in care, as well as augmenting ART regimes with financial and nutritional support while encouraging status disclosure to a trusted family member.