Abstract Background In Taiwan, illegal drug use is a critical health problem during adolescence. Schools playa vital role in preventing students’ illegal drug use. Accordingly, we developed and evaluated a school-based, drug-use prevention program integrating the theory of planned behavior (TPB) and health literacy for junior high school students. Aim This study aimed to use a theory-based program to prevent students from illegal drug use in Taiwanese junior high school students. Methods We recruited 648 junior high school students aged around 13–14 years (grades 7 to 8 students) from 14 selected schools: N = 323 in the experimental group, N = 325 in the comparison group. The experimental group received 10 45-min sessions of a theory-based drug-use prevention program. The comparison group received traditional didactic teaching and drug refusal skill training. We used a generalized estimating equation (GEE) to analyze data. Results Results of paired t-tests indicated that drug-use health literacy and TPB-related variables improved in the experimental group. The GEE analyses indicated that participants in the experimental group also demonstrated significantly improved health literacy (p