Combination HIV prevention packages have reduced HIV incidence and improved HIV-related outcomes among young people. However, there is limited data on how package components interact to promote HIV-related prevention behaviours. We described the uptake of HIV prevention interventions supported by Determined, Resilient, Empowered, AIDS-free, Motivated and Safe (DREAMS) Partnership and assessed the association between uptake and HIV-related behaviours among young people in rural KwaZulu-Natal, South Africa. We analysed two cohorts followed from May 2017 to December 2019 to evaluate the impact of DREAMS, covering 13-29 year-old females, and 13-35 year-old males. DREAMS interventions were categorised as healthcare-based or social. We described the uptake of interventions and ran logistic regression models to investigate the association between intervention uptake and subsequent protective HIV-related outcomes including no condomless sex and voluntary medical male circumcision (VMMC). For each outcome, we adjusted for socio-demographics and sexual/pregnancy history and reported adjusted odds ratios (aOR) and 95% confidence intervals (CI). Among 5248 participants, uptake of healthcare interventions increased from 2018 to 2019 by 8.1% and 3.7% for males and females respectively; about half of participants reported receiving both healthcare and social interventions each year. The most utilised combinations of interventions included HIV testing and counselling, school-based HIV education and cash transfers. Participation in social interventions only compared to no intervention was associated with reduced condomless sex (aOR = 1.60, 95%CI: 1.03-2.47), while participation in healthcare interventions only was associated with increased condomless sex. The uptake of interventions did not significantly affect subsequent VMMC overall. Among adolescent boys, exposure to school-based HIV education, cash transfers and HIV testing and counselling was associated with increase in VMMC (aOR = 1.79, 95%CI: 1.04-3.07). Multi-level HIV prevention interventions were associated with an increase in protective HIV-related behaviours emphasizing the importance of accessible programs within both school and community settings for young people.