The aerial parts of Paederia scandens (Lour.) Merr. were subjected to aqueous extraction followed by systematic isolation and purification using sequential chromatographic techniques. Twenty-one coumarins, including six previously undescribed ones, were obtained. Their structures were elucidated based on comprehensive analyses of HR-ESI-MS, NMR and ECD data. The anti-neuroinflammatory activity of the isolated coumarins was evaluated using an LPS-induced neuroinflammation model in BV-2 microglia cells. Fraxin methyl ether (2) demonstrated significant inhibition of nitric oxide (NO) production, with an IC50 value of 17.07 ± 2.88 μM. Mechanistic investigations revealed that 2 suppressed the nuclear translocation of NF-κB and downregulated the expression of pro-inflammatory mediators (iNOS, COX-2) and cytokines (IL-1β, IL-6), thereby attenuating neuroinflammatory responses. These findings provide a phytochemical basis for further development and utilization of P. scandens as a natural source of potential anti-neuroinflammatory agents.