The active compound, 4-methoxycinnamyl p-coumarate (MCC), derived from the rhizome of Etlingera pavieana (Pierre ex Gagnep) R.M.Sm., has been shown to exert anti-inflammatory effects in several inflammatory models. However, its effects on microglial cells remain elusive. In the current study, we aimed to investigate the anti-neuroinflammatory activities of MCC and determine the potential mechanisms underlying its action on lipopolysaccharide (LPS)-induced BV2 microglial cells. Our results revealed that MCC significantly reduced the secretion of nitric oxide (NO) and prostaglandin E2, concomitantly inhibiting the expression levels of inducible NO synthase and cyclooxygenase-2 mRNA and proteins. Additionally, MCC effectively decreased the production of reactive oxygen species in LPS-induced BV2 microglial cells. MCC also attenuates the activation of NF-κB by suppressing the phosphorylation of IκBα and NF-κB p65 subunits and by blocking the nuclear translocation of NF-κB p65 subunits. Furthermore, MCC significantly reduced the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), and protein kinase B (Akt)/glycogen synthase kinase-3β (GSK-3β). In addition, MCC markedly increased the expression of heme oxygenase-1 (HO-1) by upregulating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. Collectively, our findings suggest that the anti-inflammatory activities of MCC could be attributed to its ability to suppress the activation of NF-κB, MAPK, and Akt/GSK-3β while enhancing that of Nrf2-mediated HO-1. Accordingly, MCC has promising therapeutic potential to treat neuroinflammation-related diseases.