(1) Background: Mozambique has an average population age of 17 years and adolescents and youths have a pivotal role in SARS-CoV-2 pandemic control. (2) Methods: We conducted a cross-sectional study in order to assess the awareness and information needs with regard to COVID-19 among a sample of adolescents and youths from two different Mozambican provinces. (3) Results: Only 25% of adolescents and youths had a high level of awareness and only 543/2170 participants reported a high level of knowledge regarding COVID-19. In our multivariate model, significant predictors of reporting a high level of knowledge about COVID-19 include female sex (O.R. = 1.47; 95% confidence interval (CI) 1.23–2.89), having a house without a thatched roof (O.R. = 1.85; 95% CI 1.02–2.95) and HIV-positive status (O.R. = 1.56; 95% CI 1.36–2.87). (4) Conclusions: Our study highlights an important and relevant knowledge gap in adolescents and youths with respect to the COVID-19 pandemic. Involving young people and adolescents in the fight against SARS-CoV-2 is an essential strategy, especially in countries where the national average age is young, such as Mozambique, and where this epidemic can aggravate an already fragile health system.