Background: The use of drugs by teenagers is a major health concern globally. At this transitional point, secondary school students are the most vulnerable and are susceptible to risks associated with lack of knowledge of substance use. Objective: The objective of this study was to evaluate the knowledge, attitude, and practice of substance use among Nsukka secondary school students. Methods: This was a cross-sectional study using a validated, self-administered questionnaire, comprising seven sections: demographic characteristics, knowledge of substance use, attitude toward substance use, practice of substance use, contributing factors, effects of substance use, and commonly used substance. Using IBM SPSS Statistics 20, the data were analyzed. To summarize the data, descriptive analysis (frequency, percentage, mean, and standard deviations) was used. Results: Over half of the respondents were female (57.5%) and were junior secondary school students (62.2%). Most of the respondents (80%) were conscious of substance abuse. More than half (52.5%) of the respondents had good knowledge of substance usage and only 9.6% of the respondents had a negative attitude toward drug use. It was deduced from the collected data that most students never carried out substance use activities. The respondents agreed that alcohol was the commonly used substance (52.4%) and curiosity (51.7%) was the major contributing factor among school students to substance use. Conclusion: The study found that students in secondary schools had sufficient awareness and a constructive outlook toward drug use, and that the majority did not use substance. Among high school students, alcohol was the most commonly used substance.