Background: Adolescents living with HIV face unique challenges that affect health outcomes, including adherence to antiretroviral therapy (ART). Suboptimal adherence contributes to viral resistance, treatment failure, and increased morbidity. This study examined the promotive and inhibitory factors affecting drug adherence among adolescents living with HIV at the Federal Medical Centre (FMC), Ido-Ekiti, Ekiti State, Nigeria. Methods: A descriptive cross-sectional study was conducted among 272 adolescents living with HIV at FMC Ido-Ekiti. Participants were selected by systematic sampling and interviewed using a pre-tested, structured questionnaire covering sociodemographic characteristics, HIV knowledge, and predisposing and reinforcing adherence factors. Data were analysed using IBM SPSS Statistics v27.0. Chi-square tests determined associations between categorical variables (significance: p < 0.05). Results: The mean age was 16.4 ± 2 years; 51.1% were female and 85.7% were single. Health facilities were the most common information source (55.1%) and 73.2% had good HIV knowledge. Only 50.7% reported easy adherence to medication. The most prominent barrier was lack of transportation for medication refills (30.5%). Factors significantly associated with HIV knowledge included family type (p = 0.002), education level (p < 0.001), and years since diagnosis (p < 0.001). Factors significantly associated with adherence included marital status (p = 0.002), family type (p < 0.001), years since diagnosis (p < 0.001), family APGAR score (p < 0.001), and HIV knowledge level (p < 0.001). Conclusion: Despite generally high HIV knowledge, only half of the adolescents adhered adequately to ART. Transportation barriers, family type, and limited social support were key impediments. Family support and regular healthcare provider engagement promoted adherence. Targeted transport subsidies, community-based medication delivery, and strengthened social support networks are recommended.