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We aimed to estimate unbiased effects of mental health problems (MHPs) on school performance in first graders, with an emphasis on rigorous adjustment for potential confounders. A population-based prospective cohort study was performed in the area of Mainz-Bingen (Germany). In 2015, all preschoolers were approached, and the presence and type of MHP (externalising/internalising) and other physical chronic health conditions were identified by the preschool health examination and study-specific questionnaires. At the end of the first grade, school performance (reading, writing, numeracy, and science) was assessed by the class teacher and rated on a four-item scale ranging from - 8 to + 8. Of 3683 children approached, 2003 (54%) were enrolled. School performance was available for 1462 children (51% boys, mean age 7.3 years). Of these, 41% had signs of at least one MHP. Compared to children without indications of mental and physical chronic health conditions, children with MHPs had lower school performance scores [adjusted mean difference - 0.98, 95% CI (- 1.35; - 0.61); P < 0.001]. Regarding the type of MHP, externalising MHPs were associated with poor school performance [adjusted mean difference - 1.44, 95% CI (- 1.83; - 1.05); P < 0.001], while internalising MHPs were not. Children with hyperactivity inattention problems were most affected [adjusted mean difference - 1.96, 95% CI (- 2.36; - 1.56); P < 0.001]. Externalising MHPs and in particular hyperactivity inattention problems may already affect school performance in early primary school. Identification of children with externalising MHPs prior to school entry may help to prevent impaired academic achievement in affected children.