Both ageing and chronic stress are associated with altered brain plasticity, dysregulation of the immune system, and an increased risk of developing brain disorders; all of which have consequences for cognitive and emotional processing. Here we examine the similarities between behavioural changes during ageing and stress altered behaviours (anxiety, depressive-like behaviour, cognition, and sociability) in rodents and humans. The molecular mechanisms hypothesised to mediate age-related changes in brain function including dysfunction of the hypothalamic–pituitary–adrenal (HPA) axis, dysregulation of neurotransmission and neurotrophic factor signalling, increased inflammatory state, genetic and epigenetic changes, oxidative stress, metabolic changes, and changes in the microbiota–gut–brain axis are discussed. Finally, we explore how the already stressed aged brain psychologically and physiologically responds to external stressors.