Mental health issues in children and young people are frequent and can have enduring negative consequences. Preventive early interventions delivered at school may foster psychological well-being, and preliminary evidence suggests that mindfulness-based social and emotional learning (SEL) interventions have positive effects on children’s mental health. The aim of this study was to evaluate a mindfulness-based SEL curriculum including a French adaptation of the Kindness Curriculum (KC), delivered by pre-kindergarten teachers, in a cluster randomized control trial. Sixty-four classes (761 children, aged 38–58 months) from a socio-economically disadvantaged area in France were randomly assigned to either intervention or waiting-list control conditions. Indicators of children’s mental health, self-management, positive relationships with teachers and peers, emotional processing and executive functioning were collected through teacher-rated questionnaires, standardized observations, and behavioral tasks. Results in the whole sample indicated a positive effect of the intervention on children’s mental health, including a reduction in emotional, conduct and peer relationship problems, and a reduction in teacher-child conflicts. No significant effects were found on the other indicators. Heterogeneity analyses revealed stronger effects of the intervention on several indicators for children who had a teacher with lower level of teaching experience, for children with lower baseline mental health and for older children. This program therefore appears as a promising early school-based intervention promoting mental health and positive relationships, especially in a subgroup of at-risk preschool-aged children.