Introduction The efficacy of antiretroviral medicines to improve health outcomes and wellbeing depends largely on how soon they are prescribed and how PLHIV adhere to their prescribed regimens. The objectives of this cross-sectional study were to examine adherence to antiretroviral therapy (ART) and to assess perceived health and wellbeing among people living with HIV(PLHIV) in two regions in Ghana. Methods Quantitative data were collected from 301 PLHIV at three HIV clinics in Volta and Oti regions in Ghana using descriptive cross-sectional study design. Data collected included sociodemographic characteristics, ART initiation and adherence, and perception of health and wellbeing and analyzed using Statistical Package for Social Sciences (SPSS) version 20. Demographic and categorical variables were analyzed using descriptive statistics while Chi-squared analyses and binary logistics regression were used to determine variables that correlated with adherence to ART regimen. A Mann–Whitney U-test was used to measure differences in perception of health and wellbeing between male and female participants. Results 80% initiated ART within a month following diagnosis and 97.3% reported adhering to their ART regimens consistently. A Pearson χ² revealed that the availability of alternatives to the current ART medications showed a significant association with ART adherence (χ² =12.078, p= 0.002). 90% reported improvement in their health and personal wellbeing. High ART adherence and positive perceived health and wellbeing were found. Conclusion Regular supply of ART and investment in LA-ART to ensure more effective, efficient, and stress-free adherence to ART for PLHIV regardless of their residence in the country.