Background and Purpose: Metabolic and cardiovascular disease is the most prevalent disease burden in the world and risk factor for progressive cognitive decline. Evidence associates cardiovascular risk factors to unfavorable systemic and neuro-inflammation and to cognitive decline. Cardiovascular therapeutics (e.g., statins and anti-hypertensives) possess immune-modulatory functions in parallel to their cholesterol- or blood pressure (BP)-lowering properties. How their ability to modify immune responses affects cognitive function is unknown. Experimental Approach: By using flow cytometry, Elisa, qPCR, Western blotting and object recognition tasks, we examined the effect of chronic hypercholesterolemia on inflammation and memory function in Apolipoprotein E (ApoE) knockout mice and normocholesterolemic wild-type mice. Key results: Chronic hypercholesterolemia associated to moderate BP elevations and apparent immune system activation characterized by increases in circulating pro-inflammatory Ly6Chi monocytes in ApoE-/- mice. The persistent low-grade immune activation associated to chronic hypercholesterolemia facilitates the infiltration of pro-inflammatory Ly6Chi monocytes into the brain of aged ApoE-/- but not wild-type mice, linking to memory dysfunction. Therapeutic administration of cholesterol-lowering simvastatin reduced BP, systemic and neuro-inflammation, and the occurrence of memory deficits in aged ApoE-/- mice. BP-lowering therapy alone (i.e. hydralazine) attenuated some neuro-inflammatory signatures but not the occurrence of memory deficits. When administered in combination, it reduced effectiveness of statin therapy in some instances. Conclusions and Implications: Our study suggests a link between chronic hypercholesterolemia, myeloid cell activation and neuro-inflammation with memory impairment. Cholesterol-lowering therapy provides effectiveness to attenuate memory impairment and inflammatory events and hence, emerges as safe therapeutic strategy to control hypercholesterolemia-associated memory decline.