Neuropathological changes in Alzheimer's disease (AD) are directly linked to the early inflammatory microenvironment in the brain. Therefore, disease-modifying agents targeting neuroinflammation may open up new avenues in the treatment of AD. Strigolactones (SLs), subclasses of structurally diverse and biologically active apocarotenoids, have been recently identified as novel phytohormones. In spite of the remarkable anticancer capacity shown by SLs, their effects on the brain remained unexplored. Herein, the SIM-A9 microglial cell line was used as a phenotypic screening tool to search for the representative SL, GR24, demonstrating marked potency in the suppression of lipopolysaccharide (LPS)-induced neuroinflammatory/neurotoxic mediators by regulating NF-kappa B, Nrf2, and PPAR gamma signaling. GR24 also in the brain endothelial cell line bEnd.3 mitigated the LPS-increased permeability as evidenced by reduced Evans' blue extravasation through enhancing the expression of tight junction protein, occludin. Collectively, the present work shows the anti-neuroinflammatory and glia/neuroprotective properties of GR24, making SLs promising scaffolds for the development of novel anti-AD candidates.