Postnatal depression (PND) is common and predicts a range of adverse maternal and offspring outcomes. PND rates are highest among women with persistent mental health problems before pregnancy, and antenatal healthcare provides ideal opportunity to intervene. We examined antenatal perceived social support as a potential intervention target in preventing PND symptoms among women with prior mental health problems. A total of 398 Australian women (600 pregnancies) were assessed repeatedly for mental health problems before pregnancy (ages 14-29 years, 1992-2006), and again during pregnancy, two months postpartum and one year postpartum (2006-2014). Causal mediation analysis found that intervention on perceived antenatal social support has the potential to reduce rates of PND symptoms by up to 3% (from 15 to 12%) in women with persistent preconception symptoms. Supplementary analyses found that the role of low antenatal social support was independent of concurrent antenatal depressive symptoms. Combined, these two factors mediated up to more than half of the association between preconception mental health problems and PND symptoms. Trialling dual interventions on antenatal depressive symptoms and perceived social support represents one promising strategy to prevent PND in women with persistent preconception symptoms. Interventions promoting mental health before pregnancy may yield an even greater reduction in PND symptoms by disrupting a developmental cascade of risks via these and other pathways. This article is part of the theme issue ‘Multidisciplinary perspectives on social support and maternal-child health’