Pre-exposure prophylaxis (PrEP) is an effective HIV prevention strategy for high-risk populations, including adolescent girls and young women (AGYW) and adolescent boys and young men (ABYM). While various PrEP-delivery models exist in South Africa, little is known about optimizing PrEP-uptake and adherence for AGYW and ABYM. This study explored preferred and feasible PrEP care models to enhance initiation and adherence among at-risk adolescents and young adults (AYAs) in a high-HIV prevalent rural district in South Africa. We conducted a longitudinal, population-based cohort study from August 2021 to July 2022 across 22 service delivery points (SDPs) in KwaZulu-Natal. High-risk, sexually active HIV-negative AGYW (15-24 years) and ABYM (15-35 years) were recruited from clinics, schools, and community-based youth zones. PrEP-uptake and adherence, based on national guidelines, were assessed using Pearson's Chi square test and binomial regression. Of 2,772 HIV-negative AYA, 781 (28%) initiated PrEP. Despite 65% being classified as high risk for HIV (p < 0.001), only 22% initiated PrEP. Initiation was higher in female (82%, p < 0.001) and among the 15-19 years (51%, p = 0.11). PrEP uptake varied significantly by SDPs, lowest in clinics (9%, p < 0.001), higher in youth zones (58%, p < 0.001), and highest in schools (73%, p < 0.001). Adherence declined significantly over time, dropping from 12% at one month to 2% at six months (p < 0.001). These findings highlight the need for targeted interventions in schools and communities, addressing barriers such as awareness, side effects, and accessibility. Expanding PrEP services to non-traditional settings may enhance uptake and adherence, reducing HIV risk among young people.