Background Childhood dysregulation, which reflects deficits in the capacity to regulate or control one's thoughts, emotions and behaviours, is associated with psychopathology throughout childhood and into adulthood. Exposures to adversity during the prenatal period, including prenatal depression, can influence the development of dysregulation, and a number of candidate genes have been suggested as moderators of prenatal exposure, including polymorphisms in the promoter region of the serotonin transporter gene (5‐HTTLPR). We examined whether prenatal depression and child 5‐HTTLPR interact to predict childhood dysregulation. Method Sample of N = 213 mother–child pairs from the Maternal Adversity, Vulnerability and Neurodevelopment (MAVAN) project. Mothers reported the IBQ‐R at 3 and 6 months, and the ECBQ at 18 and 36 months, from which measures of dysregulation were extracted. Mothers' self‐reported symptoms of depression on the CES‐D at 24–36 weeks of gestation, and at 6, 12, 24 and 36 months postnatal. 5‐HTTLPR genotype was extracted from buccal swabs. Mixed‐model and confirmatory analyses were conducted. Results Prenatal depression and 5‐HTTLPR interacted to predict dysregulation from 3 to 36 months, within a model of strong differential susceptibility. Conclusion Children with S or LG alleles, when exposed to prenatal depression, have higher levels of dysregulation, and when exposed to lower or little prenatal depression, have higher capacity for regulation. Our findings support efforts to identify, support and treat prenatal depression.