Neuroinflammation is a key mechanism against infection, injury, and trauma in the central nervous system (CNS). The heartwood of Dalbergia odorifera T. Chen is an important source of traditional Korean and Chinese medicines. (2R, 3R)-Obtusafuran (1) and isoparvifuran (2) are arylbenzofuran compounds isolated from D. odorifera. This study determined the efficacy of (1) and (2) in modulating the regulation of anti-inflammatory activity through the upregulation of heme oxygenase (HO)-1 in BV2 microglia. Compound (1) inhibited the protein expression of inducible nitric oxide synthase (iNOS), iNOS-derived nitric oxide (NO), cyclooxygenase (COX)-2, and COX-2-derived prostaglandin E2 (PGE2) in lipopolysaccharide (LPS)-stimulated mouse BV2 microglia. (2R, 3R)-Obtusafuran (1) also reduced tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) production, and these anti-neuroinflammatory effects were shown to be correlated with the suppression of the phosphorylation and degradation of inhibitor of nuclear factor kappa B-α (IκB-α), and nuclear factor kappa B nuclear (NF-κB) translocation and DNA binding activity. In addition, (1) upregulated HO-1 expression via nuclear translocation of nuclear factor E2-related factor 2 (Nrf2) in mouse BV2 microglia. Using tin protoporphyrin (SnPP), an HO activity inhibitor, we verified that the inhibitory effects of (1) on the proinflammatory mediators and proteins were associated with the induction of HO-1 expression. Activated microglia-mediated cell death of mouse hippocampal HT22 cells was significantly repressed by (1). Our data suggest that (2R, 3R)-obtusafuran (1) has therapeutic potential against neurodegenerative diseases caused by neuroinflammation.