Substance abuse is a huge global health and critical problem which has made it a matter of significant public health importance in most countries. Substance abuse poses a significant threat to the health, social and economic fabric of families, communities and nations. This study examined the level of knowledge and attitude of youths to substance abuse in Alimosho Local Government; the most populous Local Government Area in Lagos State. The study was aimed at exploring the general knowledge of substance abuse among youths; examining the relationship between youths' knowledge of substance abuse and substance use; exploring their attitude to substance abuse and proffer possible strategies that can be employed to address substance abuse among youths in order to ameliorate the growing problem substance abuse in youth population. A cross-sectional study design was employed to select youths within the age range of 18 -35 years for the study. A sample size of 350 was selected and 340 analysable questionnaires were returned (attrition rate of 3%). Self-structured validated questionnaire was administered. The questionnaire was divided into three sections: Socio-demographics of the participants, Knowledge on drug abuse, attitudes and perception towards drug abuse. The statistical analyses of frequency counts, percentages and Pearson's Chi square using the Statistical Package of Data Analysis (SPSS) 2012 to test the hypotheses at 0.05 significance level. Findings showed adequate knowledge of the risks of substance abuse among youths and there was indifference in the attitude of youths to the use of drugs. In conclusion, the negative attitude of youths to substance abuse is a cause for concern since the youths are the future of the nation. It was recommended that health education intervention, stressing the health implications of substance abuse and how to come off substance abuse through psychotherapy should be put in place.