Alzheimer's disease is a major cause of dementia in humans. The appearance of cognitive decline is linked to the overproduction of a short peptide called β-amyloid (Aβ) in both soluble and aggregate forms. Here, we show that injecting macrophage colony-stimulating factor (M-CSF) to Swedish β-amyloid precursor protein (APP_Swe)/PS1 transgenic mice, a well-documented model for Alzheimer's disease, on a weekly basis prior to the appearance of learning and memory deficits prevented cognitive loss. M-CSF also increased the number of microglia in the parenchyma and decreased the number of Aβ deposits. Senile plaques were smaller and less dense in the brain of M-CSF-treated mice compared to littermate controls treated with vehicle solution. Interestingly, a higher ratio of microglia internalized Aβ in the brain of M-CSF-treated animals and the phagocytosed peptides were located in the late endosomes and lysosomes. Less Aβ₄₀ and Aβ₄₂ monomers were also detected in the extracellular protein enriched fractions of M-CSF-treated transgenic mice when compared with vehicle controls. Finally, treating APP_Swe/PS1 mice that were already demonstrating installed Aβ pathology stabilized the cognitive decline. Together these results provide compelling evidence that systemic M-CSF administration is a powerful treatment to stimulate bone marrow-derived microglia, degrade Aβ and prevent or improve the cognitive decline associated with Aβ burden in a mouse model of Alzheimer's disease.