Purpose: This study was to explore the effect of preventive health education intervention in the knowledge, attitude, practice of betel nut chewing, and self-efficacy of anti-betel nut chewing for adolescent students. Methods: One hundred eighty-six indigenous samples were recruited, and divided into experimental and control groups. The experimental group underwent fourteen-week classes regarding the prevention of betel nut chewing. Both groups took post-tests immediately after intervention in order to evaluate the instant effect of the teaching program. The follow-up (post-post-test) evaluated the instant improvement at the 28th week (14 weeks after the end of the class). Results: There was no difference in knowledge of the hazards of betel nut chewing among pre-tests, post-tests, and post-post-test in the experimental group. The attitude, practice of betel nut chewing and self-efficacy of anti-betel nut chewing aspects was significantly different among pre-tests, post-tests, and post-post-test after intervention. There was a significantly immediate and instant improvement after health education intervention. Conclusion: Health education enables students to better resist the use of betel nuts. This study confirmed the importance of health education programs in dealing with the health risks of betel nut chewing for the risk group Students. (Contains 4 tables.)