Based on theoretically driven models, the Chicago School Readiness Project (CSRP) targeted low-income children’s school readiness through the mediating mechanism of self-regulation. The CSRP is a multicomponent, cluster-randomized efficacy trial implemented in 35 Head Start–funded classrooms (N = 602 children). The analyses confirm that the CSRP improved low-income children’s self-regulation skills (as indexed by attention/impulse control and executive function) from fall to spring of the Head Start year. Analyses also suggest significant benefits of CSRP for children’s preacademic skills, as measured by vocabulary, letter-naming, and math skills. Partial support was found for improvement in children’s self-regulation as a hypothesized mediator for children’s gains in academic readiness. Implications for programs and policies that support young children’s behavioral health and academic success are discussed.