The field test of The Science of Mental Illness curriculum supplement for middle school (grades 6–8) children provided an opportunity to assess knowledge and attitudes about mental illness in more than 1,500 middle school students throughout the United States and to evaluate the impact of an educational intervention on stigma-related attitudes. Two primary questions were examined: (1) what are the baseline knowledge and attitudes about mental illness in this sample of middle school students, and (2) does participation in a curriculum about the science of mental illness increase knowledge and improve attitudes about mental illness? Consistent with findings from other studies, results indicate that students had some understanding of mental illness as a problem of the brain with biological and psychosocial causes; however, they lacked knowledge about treatment and overall were “not sure” about many aspects of mental illness. The students did not strongly endorse negative attitudes about mental illness at baseline. The curriculum produced significant improvements in both knowledge and attitudes at posttest and was most effective in improving attitudes among those with more negative baseline attitudes. These findings suggest that a brief educational program can be an effective intervention to increase knowledge and improve attitudes about mental illness.