Introduction: Majority of youths all over the world ignorantly rely on one or more types of drugs for their everyday activities, including Mandrax, Cocaine, Tobacco, Heroine, Khat, Morphine, Alcohol, Amphetamines, Ephedrine, and Glue among others. This study’s purpose was to evaluate the epidemiology of substance abuse among the youths in Makueni County, Kenya. The broad objectives that guided the study was; to determine the epidemiology of substance abuse among the youths in Makueni County, Kenya. Methodology: -A Cross-sectional mixed-method study design was undertaken, with the target population consisting of all youths from Makueni County's eight main marketplaces. Purposive sampling was employed to obtain the 8 Major urban centres while simple random selection approach was employed to obtain respondents in each market. Qualitative data was collected using 8 key informants to supplement the quantitative data collected from the youths. A self-administered questionnaire was employed. Quantitative data was analysed using Descriptive as well as inferential statistics while qualitative narrative data was grouped into themes and was presented inform of texts with verbatim quotes used to amplify the voice of the informants. Results: The study sampled 384 respondents from Makueni County. Prevalence of Drug/Substance abuse stood at 62.3 % with alcohol (58.3%) being the most commonly abused drug/Substance. Hard Drugs were the least abused with 96.9% reporting they had never abused. Pearson correlation between gender, age and education level on prevalence of drug abuse in Makueni showed a weak positive relationship(r=0.032), weak negative relationship (r=-0.064) and a significant negative relationship (r=-0.212) respectively. High unemployment rates 62.3%, easy availability of drugs 34.3%, Peer pressure 72.3%, cheap cost of drugs 28.3% and poverty level 15.1% are main contributory factors to drug abuse. A chi-square run on the factors contributing to drug abuse also indicated a significant positive relationship between the local music, TV programs, friends, and social media with prevalence of drug abuse in Makueni County. The chi-square results also revealed a weak positive relationship between parents and prevalence of drug abuse in Makueni County. Faith-based organizations, local leaders, religious leaders, and non-governmental organizations had a strong negative relationship with prevalence of drug abuse in Makueni County. Conclusion & Recommendations: There is high prevalence of Drug/Substance abuse among the youths in Makueni County and both the County Government, national Government and the community in general must put stringent measures to curb the easy availability, sale and buying of abusive Drugs and other substances in the county.