Despite initiatives by the WHO and the International AIDS Control Program, including free HIV screenings and antiretroviral therapy (ART), many adolescents and young adults struggle with treatment compliance. This study aimed to assess ART compliance among HIV-positive adolescents and young adults and evaluate their sense of well-being at the Buea Regional Hospital. A cross-sectional study was conducted from June 1 to August 31, 2022, using a convenient sampling technique to enroll 150 consenting participants. A structured questionnaire gathered data on demographics and ART compliance. Data analysis was performed using SPSS version 26 and Excel 2013, with a significance level set at 0.05. Results indicated an overall compliance rate of 68.7%. Notably, participants reported that feeling depressed was significantly linked to both adherence to and discontinuation of medication (p=0.016 and p=0.010, respectively). The most common emotional struggle was a lack of interest in daily tasks, affecting 16.4% of respondents. Despite these challenges, 76.0% of participants reported a positive sense of well-being, indicating minimal distress in the preceding two weeks. In conclusion, HIV remains a prevalent chronic viral infection among adolescents and young adults. Understanding the factors influencing compliance with ART at the Buea Regional Hospital is critical for enhancing treatment outcomes and improving the overall well-being of this demographic. Addressing mental health and emotional support may be vital in improving adherence rates.