Background: Despite all the strategies put in place by WHO and the International AIDS control program, such as free HIV screening and free distribution of ART’s, large numbers of adolescents and young adults still find it difficult to comply with their treatment regimens. Hence, the purpose of this study to identify the barriers and factors facilitating compliance and non-compliance to ART among HIV positive adolescents and young adults and to evaluate the sense of well-being of the patients receiving treatment at the Buea Regional Hospital. Methodology: A cross-sectional study design was carried out at the Buea Regional Hospital from June 1st to August 31st, 2022. A convenient sampling technique was used to enroll consented participants, whereby a structured questionnaire was administered as they came to the treatment center for their appointments. Data was collected from respondents on demographic characteristics, compliance to ART was evaluated using a well-structured questionnaire. The data was analyzed using SPSS version 26 and Excel 2013 at 0.05 significance level. Results: Out of the 150 participants, an overall compliance rate of 68.7% was observed against a non-compliance rate of 31.3%. Taking medication when feeling depressed was significantly (p=0.016) associated to compliance with treatment than sometimes not taking medications when feeling depressed. Moreover, stopping to take medication when feeling depressed was significantly (p=0.010) associated with compliance compared to sometimes not taking medication when feeling depressed. The factors associated with non-compliance were; taking medication when feeling depressed significantly (p=0.016) associated with non-compliance than not taking medication when feeling depressed. Not taking medication sometimes when feeling depressed significantly (p=0.010) associated with non-compliance than not taking medication when feeling depressed. The highest percentage scored for being worried (over the last two weeks) resulted from the fact that most of the participants had little interest in carrying out daily tasks (16.4%). Nevertheless, majority of respondents (76.0%) had a very good sense of well-being characterised by minimal levels of being bothered over the last two weeks. Conclusion: The factors associated with compliance to ART have been categorised as religious, cultural, family and community factors; patient related factors; socio-economic factors; work place related factors; and health care team and system related factors. Some factors such as a female gender, age greater than 49 years, higher levels of education, positive perceptions of treatment, high motivation, satisfaction with information provided by physician and higher CD4 count at initiation of ART were also identified.