Several studies in Asia, USA and the United Kingdom have shown widespread drug use among adolescents and young adults, thus drawing global attention to this problem. There is however a paucity of data on drug use among youths in rural Nigeria. The target population for this study were adolescents and youths from three out of the 6 senior secondary schools in Igboora, Nigeria, selected by simple random sampling. A cross-sectional study, using interviewer-assisted questionnaire to determine the prevalence of and identify factors associated with drug use. Two hundred and seventy three (69.3%) respodents were currently using one or more drugs of which 123 (45.1%) were single drug users while 150 (54.9%) were multiple drug users. Fourteen different psychoactive substances were reportedly used of which Alabukun, a popular, locally manufactured analgesic (a mixture of acetyl salicylic acid and caffeine) was the most commonly reported drug currently used and ever used. Alcohol was the next commonly reported currently used drug while Kolanut was the next commonly ever-used drug. Tobacco ranked low on the list with only 1.5% current users, while 4.4% reported having ever-used this drug. Following logistic regression analysis, having peers (close friends) and primary caretakers who use drugs, significantly increased the chances of the students using drugs (P < 0.001, P < 0.001). Males compared with females were also significantly more likely to use drugs (P = 0.024). Significant relationship exists between drug use and poor role modeling. Introducing peer counseling, community awareness and working with adults who have adolescents at home would go a long way towards reducing psychoactive drug use at community and household level, particularly among in-school youths.