The disproportionate smoking prevalence among adolescents in rural Taiwan may be attributed to insufficient anti-smoking education. Increasing access to such education may help reduce initiation and promote smoking cessation in adolescents, particularly in rural areas. However, effects of these programs require verification. This study determined the effectiveness of a school-based prevention program in enhancing knowledge, attitudes, and anti-smoking exposure self-efficacy among seventh-grade non-smoking students. A quasi-experimental design with convenience sampling was employed, where participants included seventh graders from two junior high schools who completed a questionnaire 1−2 weeks before and after the intervention. Furthermore, the intervention group received four smoking and secondhand smoke (SHS) prevention classes, whereas the control group engaged in scheduled school activities. Knowledge on smoking (B = 4.38, p < 0.001) and SHS (B = 2.35, p < 0.001) were significantly greater in the intervention group. Moreover, the groups differed significantly in avoiding SHS exposure (B = 3.03, p = 0.031). Intervention modifications may be necessary to enhance the program’s effect on smoking exposure-related attitudes and self-efficacy. Additionally, cultural and other aspects (or “urban-rural gap”) might influence these results. Future randomized controlled trials should compare urban to rural adolescents, use longitudinal designs, and assess smoking initiation or cessation.