The early stress of maternal separation (ES) exerts long-lasting effects on cognition and anxiety. Recent evidence indicates enhanced hippocampus-dependent spatial learning in young adult ES animals, which shifts towards a decline in long-term memory in middle-aged life. Further, we find that ES animals exhibit enhanced anxiety in young adulthood that does not persist into middle-aged life. Here, we demonstrate unique, predominantly non-overlapping, hippocampal transcriptomes in young adult and middle-aged ES animals that accompany the temporally-specific behavioural consequences. Strikingly, the extent of gene dysregulation in middle-aged ES animals was substantially higher than in young adulthood. Functional analysis revealed distinct biological processes enriched at the two ages, highlighting the temporal shift in ES-evoked gene regulation. Our results suggest that ES history interacts with aging to exacerbate age-associated transcriptional changes and cognitive decline. qPCR profiling of histone deacetylases (Hdacs) and histone methyltransferases (HMTs) revealed an age-dependent, opposing regulation with decreased expression noted in young adult ES animals (Hdac 2, 7, 8, 9 and Suv39h1) and enhanced levels in middle-aged life (Hdac 2, 6, 8 and Suv39h1). While altered expression of histone modifying enzymes did not translate into global histone acetylation or methylation changes, we noted differential enrichment of histone acetylation and methylation modifications at the promoters of multiple genes regulated in the hippocampi of young adult and middle-aged ES animals. Our results highlight the differential molecular and behavioural consequences of ES across a life-span, and suggest a possible role for epigenetic mechanisms in contributing to the temporally-specific transcriptional changes following ES.