Significance Since Down syndrome (DS) is caused by trisomy of chromosome 21, prenatal diagnosis of DS is now possible. Nonetheless, parents of a fetus diagnosed with DS have only two choices: terminate the pregnancy or prepare to raise a child with a serious disability. We developed a new compound, ALGERNON (altered generation of neurons), to provide a third option to these parents. Treatment of pregnant dams with ALGERNON prevented morphological brain abnormalities including a thinned cortical plate. Remarkably, these offspring exhibited normal cognitive behavior compared with untreated offspring with DS. ALGERNON has therapeutic potential for treating not only DS, but also numerous neurodevelopmental disorders.