Marine algae are rich sources of biologically active compounds that may present useful leads in the development of pharmaceuticals, nutraceuticals, and functional foods. The main aim of this study was to identify the possible anti-inflammatory effects of Distromium decumbens in nasal polyp-derived fibroblasts (NPDFs) and its associated mechanism of action. NPDFs were stimulated by Pseudomonas aeruginosa lipopolysaccharide (PA-LPS) and treated with an ethanolic extract of Distromium decumbens (DDE). The production of interleukin-6 (IL-6) and IL-8 in the supernatant, the phosphorylation of mitogen-activated protein kinase (MAPK) molecules [extracellular signal-related kinase 1/2 (ERK1/2), c-Jun N-terminal kinase and p38 MAPK] and Akt, and the activation of nuclear factor-κB (NF-κB) were assayed in the PA-LPS-stimulated NPDFs untreated or treated with DDE. The expression levels of IL-6 and IL-8 in PA-LPS-exposed NPDFs were detected using enzyme-linked immunosorbent assays. The mechanisms by which DDE regulates cellular signaling cascades were investigated using electrophoretic mobility shift assays and western blot analysis. Functional validation was performed by measuring the inhibitory effects of DDE on neutrophil migration in vitro. DDE reduced the expression of IL-6 and IL-8 stimulated by PA-LPS in NPDFs. The activation of ERK1/2, Akt and NF-κB by PA-LPS was inhibited by DDE. Inhibitors of ERK1/2, Akt and NF-κB inhibited the expression of IL-6 and IL-8. In addition, DDE significantly attenuated PA-LPS-induced migration of differentiated HL-60 cells. The present findings suggest that DDE potently inhibits inflammation through the ERK1/2, Akt and NF-κB signaling pathways in NPDFs.