Brown seaweed is a rich source of fucoidan, which exhibits a variety of biological activities. The present study discloses the protective effect of low molecular weight fucoidan (FSSQ) isolated from an edible brown alga,Sargassum siliquastrum,on lipopolysaccharide (LPS)-stimulated inflammatory responses in RAW 264.7 macrophages. The findings of the study revealed that FSSQ increases cell viability while decreasing intracellular reactive oxygen species production in LPS-stimulated RAW 264.7 macrophages dose-dependently. FSSQ reduced the iNOS and COX-2 expression, inhibiting the NO and prostaglandin E2production. Furthermore, mRNA expression of IL-1β, IL-6, and TNF-α was downregulated by FSSQ via modulating MAPK and NF-κB signaling. The NLRP3 inflammasome protein complex, including NLRP3, ASC, and caspase-1, as well as the subsequent release of pro-inflammatory cytokines, such as IL-1β and IL-18, release in LPS-stimulated RAW 264.7 macrophages was inhibited by FSSQ. The cytoprotective effect of FSSQ is indicated via Nrf2/HO-1 signaling activation, which is considerably reduced upon suppression of HO-1 activity by ZnPP. Collectively, the study revealed the therapeutic potential of FSSQ against inflammatory responses in LPS-stimulated RAW 264.7 macrophages. Moreover, the study suggests further investigations on commercially viable methods for fucoidan isolation.