Mindfulness-based interventions (MBIs) in the school context are increasingly widespread worldwide. The present study evaluates the effectiveness of a school-MBI (GrowingUp Breathing program) on children's socio-emotional and academic development. Three hundred thirteen elementary students from 7 to 12 years old from two schools in Madrid (Spain) participated. A cluster-randomized control trial was designed, assigning eight classrooms to the MBI-group (N = 155) and eight classrooms to the waiting-list control group (N = 158). Measures were evaluated at pre- and post-intervention in both groups and a 3-month follow-up was collected in the MBI-group. Children self-reported their mindfulness skills (i.e., dispositional mindfulness and psychological inflexibility) and well-being (i.e., anxiety and life satisfaction) and teachers evaluated children's social-emotional competence (i.e., emotion regulation, peer-relationship problems, and prosociality), well-being (i.e., emotional symptoms), and academic competence (i.e., student engagement and academic achievement). Mindfulness skills and emotional regulation were examined as potential mediators. Results revealed that children who received the MBI, compared to children in the WLC-group, improved their mindfulness skills, emotion regulation, prosociality, and emotional and behavioral engagement and decreased anxiety and peer-relationship problems. Positive changes in dispositional mindfulness led to reductions in children's anxiety and psychological inflexibility. Positive changes in emotional regulation led to improvements in prosociality and student engagement and decreased peer-relationships problems and emotional symptoms. Therefore, the results showed that a brief-MBI integrated in the Spanish regular school curriculum enhanced children's socio-emotional and academic development. Dispositional mindfulness and emotion regulation work as processes of change that underlie the intervention's impact.