Phlebodium decumanum (Willd.) J. Sm. (P. decumanum) and other tropical ferns commonly known as Calaguala have been traditionally used as an herbal medicine by the indigenous people of Honduras. The present communication investigates the effect of P. decumanum extract on BV2 microglial cells activated with lipopolysaccharide (LPS). The activation level of BV2 cells was determined by quantifying the presence of nitric oxide (NO) in the culture supernatant by the Griess reaction. The expression of inducible nitric oxide synthase (iNOS) was visualized by immunofluorescence. The extract significantly attenuated, in a dose-dependent manner, NO production and iNOS expression induced by LPS. Our results provide the first comprehensive in vitro evidence of its anti-neuroinflammatory properties. Thus, P. decumanum extract represents a promising therapeutic agent for neurodegenerative and related inflammatory diseases.