Abstract Tobacco and drug use remain major public health concerns. The aim of this study was to evaluate the effectiveness of a school health intervention program using life skills training (LST) to reduce tobacco and drug use among Thai high school students. A randomized pretest and post-test comparative design was used to evaluate the effectiveness of the LST program. A total of 170 Thai students in grades 7–12 were randomly selected. The students in the control group received the tobacco and drug education curriculum normally provided; the intervention group received a LST program that provided information and skills specifically related to drug and tobacco use. Students in the school health intervention program had statistically significant positive effects regarding knowledge level, attitudes, and the development of refusal, decision-making, and problem-solving skills. The results showed that a LST program was effective for preventing tobacco and drug use in Thai high school students.