High levels of adherence to antiretroviral therapy (ART) are essential to promoting viral suppression and consequential good treatment outcomes. Adolescents living with HIV (ALHIV) in sub-Saharan Africa are less adherent to ART compared to adults, leading to lower rates of viral suppression and immunological recovery. We conducted a mixed-method study utilizing a convergent parallel approach to explore factors associated with ART adherence among ALHIV in the era of isoniazid preventive therapy (IPT) as part of HIV care. The quantitative data were collected from patient records from the period between 1 February 2017 and 31 January 2018 (6 months before and after IPT introduction), while qualitative data was collected from purposively selected patients and healthcare workers by in-depth interviews through a pretested interview guide. A total of 385 patient records (age 10–19 years) were analyzed in the two time periods, while 16 ALHIV (age 10–19 years) and three healthcare workers directly involved in adolescent care were interviewed. Quantitative data utilized logistic regression to measure the strength of association between IPT addition and ART adherence, whereas, qualitative data were analyzed using a thematic analysis approach. The mean age of participants in the quantitative section was 14.3 years (SD 2.7) and 178 were females, while the median age for adolescents interviewed was 14 (IQR 12–17) and 8 were females. Overall, we found an interaction of factors that influenced ART adherence. Added pill burden, on its own, did not affect ART adherence. Commonly reported factors that led to poor adherence were lack of status disclosure within the family, school pressure, and inadequate support from guardians and parents. According to retrospective patient records, complex ART regimens also worsened adherence (p = 0.0462). ART regimen was independently associated with adherence (OR 2.11 95% CI 0.97–4.53). Being on ART for a longer duration, enrolment into teen clubs, clinical psychosocial support, and self-reinforcement techniques were suggested to improve ART adherence. The interplay of multiple factors leads to poor rates of adherence. The introduction of IPT to ART packages may not independently affect ART adherence. Readily available psychosocial services and the presence of peer and guardian support is critical to optimal ART adherence. There is a need for ART centers that provide HIV care to adolescents to consider integrating psychosocial and other youth-friendly services into day-to-day clinic operations.