In combatting COronaVIrus Disease 2019 (COVID-19), immunization is the most prominent strategy. However, vaccination hesitancy—meaning delays in accepting or denying inoculation regardless of availability—has been identified as an essential threat to global health. Attitudes and perceptions play a pivotal role in vaccine acceptability. Meanwhile, uptake in South Africa’s rollout has been particularly disappointing among youths. For that reason, we explored attitudes and perceptions of COVID-19 in 380 youths in Soweto and Thembelihle, South Africa, between April and June 2022. A staggering hesitancy rate of 79.2 percent was recorded (301/380). We found negative attitudes and confounded perceptions of COVID-19 to be fueled by medical mistrust and misinformation, with online channels as the main sources of non- and counterfactual claims stemming mostly from unregulated social media popular with youths. Understanding its underpinnings—and enhancing means of curbing vaccine hesitancy—will be paramount in boosting uptake in South Africa’s immunization program, particularly among youths.