Early-life stress has been shown to disrupt the programming of the hypothalamic-pituitary-adrenal (HPA) axis which may have severe consequences in the development of neurological disorders later on in life. Prolonged early-life stressful events produce an exaggerated stress hormone response in the adult offspring. Chronic stress and elevated corticosterone levels have been found to exaggerate functional deficits and accelerate loss of dopamine producing neurons in a rat model of Parkinson’s disease. We investigated the neuroprotective effects of caffeine on 6-OHDA lesioned rats that were exposed to maternal separation stress. We examined behaviour of animals before and after the infusion of 6-OHDA using the step and cylinder tests. We also measured dopamine concentration in the striatum, mitochondrial membrane potential in the striatum and the total antioxidant capacity in blood plasma. Maternally separated rats displayed an impaired ability to initiate movement in the step test and a decreased percentage impaired limb use in the cylinder test. In the rats that received caffeine these motor deficits were ameliorated. Maternal separation exaggerated the lesion caused by 6-OHDA injection. However, the neuroprotective effects of caffeine were evident in both the stressed and non-stressed rats as shown by the higher dopamine concentration and total antioxidant capacity on caffeine treated rats. Maternally separated rats had higher mitochondrial membrane permeability when compared to the caffeine treated rats. We therefore conclude that caffeine ameliorated the neurodegeneration associated with 6-OHDA injection in maternally separated animals.