Using data from a predominantly low-income, population-based prospective longitudinal sample of 1292 children followed from birth, indicators of children's autonomic (salivary alpha-amylase; sAA) and hypothalamic–pituitary–adrenal (HPA) axis (salivary cortisol) activity at 7, 15, and 24 months of age were found to predict executive functioning at 36-months and academic achievement in pre-kindergarten. The findings suggested that the respective cortisol and sAA effects on executive functioning and academic achievement were interactive. Optimal developmental outcomes were associated with asymmetrical cortisol/sAA profiles. Higher cortisol levels were predictive of lower executive functioning and academic abilities, but only for those with concurrently moderate to high levels of sAA. In contrast, higher sAA concentrations were predictive of better executive functioning and academic abilities, but only for those with concurrently moderate to low levels of cortisol. These relations were statistically identical across infancy and toddlerhood. The conditional effects of cortisol and sAA on pre-kindergarten academic achievement were mediated fully by links between these early physiological indicators and executive functioning.