Uncontrolled drug and substance use (DSU) may pose unprecedented threats to nation building and a country’s socioeconomic development. Despite considerable efforts made and resources used to address DSU concerns, Malaysia has seen a significant annual rise in cases of DSU. The bulk of the reported cases originate from youth between the ages of 15 and 40 years. To date, data related to DSU in Malaysia have been entirely dependent on operation statistics, arrest counts, and reported cases; DSU may therefore be under-reported and the data obtained not representative at the national level. This study aims to determine the prevalence of DSU among Malaysian youth through a large nationwide representative survey. Of the population of 11,129,316 youth aged 15–40 years, the prevalence of DSU among lifetime users was found to be 5.5%, while for those who had taken drugs in the past 30 days or who currently use them, the prevalence of DSU was found to be 3.5%. The most popular drugs for lifetime users were kratom or Mitragyna speciosa, while for current users the most popular drug was cannabis. The current study reports the magnitude of the problem at a country-wide level, which is a crucial preliminary effort for crafting evidence-based and well-informed policies.