Chronic neuroinflammation is a key component of many neurodegenerative disorders. Chronic activation of this process produces pro-inflammatory cytokines, prostaglandins and reactive oxygen species that induce brain injury and neuronal dysfunction. Agave species contain saponins, compounds with anti-inflammatory activity. Extracts from A. tequilana (At), A. angustifolia (Aan), A. Americana (Aam) (125 mg/kg) and cantalasaponin-1 (5 and 10 mg/kg, isolated from Aam) were administered to male ICR mice with lipopolysaccharide (LPS)-induced neuroinflammation, after which inflammatory cytokines were measured in brain homogenates by using an enzyme-linked immunoassay (ELISA) test. All agave extracts and cantalasaponin-1, reduced brain concentration of LPS-induced pro-inflammatory cytokines IL-6 and TNF-α. Moreover, Cantalasaponin-1 increased the brain concentration of the anti-inflammatory cytokine IL-10. Agave extracts and derived compounds show promising results in the development of novel drugs for neuroinflammatory disease therapy.