<p>Cognitive decline is a hallmark of neurodegenerative diseases. The complex pathophysiology of these diseases has limited the efficacy of current therapies. The co-administration of epidermal growth factor (EGF) and growth hormone-releasing peptide 6 (GHRP6) emerges as a promising neuroprotective candidate. The present study evaluated the therapeutic potential of this combination in two preclinical models of cognitive impairment: (i) age-related decline and (ii) impairment induced by intracerebroventricular administration of streptozotocin (STZ). In both experiments, C57BL/6 mice were used and distributed into three experimental groups, each comprising 14–15 animals per group. Cognitive and motor function was assessed through gait pattern, Y-maze and novel object recognition tests. Differential gene expression was analyzed using qPCR. Both models reproduced hallmark features of cognitive decline, including deficits in working and spatial memory and changes in the expression of genes associated with oxidative stress, neuroinflammation and synaptic plasticity. In aged animals, EGF + GHRP6 treatment increased step length (<i>p</i> = 0.04). In the forced alternation Y-maze test, aged-EGF + GHRP6 animals made more visits to the novel arm than to the familiar arm 1 (<i>p</i> = 0.001) or to the familiar arm 2 (<i>p</i> = 0.04). Cognitive benefits were also observed in the STZ-induced model. STZ-EGF + GHRP6 group exhibited an alternation percentage higher than the STZ-vehicle group (<i>p</i> = 0.03). Moreover, EGF + GHRP6 treatment significantly increased the expression of genes associated with antioxidant defense (<i>Hmox1</i>), synaptic plasticity (<i>Creb1</i>), and oligodendrocyte differentiation (<i>Olig1</i>) while concurrently reducing the expression of <i>Nfkb1</i>. These findings highlight the therapeutic potential of EGF + GHRP6 co-administration as a neuroprotective strategy to mitigate neurodegeneration and preserve cognitive function.</p>