Euphorbia hirta has anti-inflammatory effects in traditional medicine, but its anti-inflammatory mechanism has not been explored at the cellular and molecular levels. To unravel these mechanisms, the main active components in the 65 and 95% ethanol extracts of Euphorbia hirta were first identified by UPLC-Q-TOF/MS. Subsequently, potential anti-inflammatory targets and signaling pathways were predicted using network pharmacology and experimentally validated using RT-PCR and flow cytometry in a lipopolysaccharide (LPS)-induced inflammation model of RAW264.7 cells. The results revealed flavonoids as the key active components. Network pharmacology uncovered 71 potential anti-inflammation targets, with a protein-protein interaction (PPI) network highlighting 8 cores targets, including IL-6, TNF, NFκB and Nrf2 et al. Furthermore, Euphorbia hirta exerts anti-inflammation effects through modulation of Nrf2 and NF-κB signaling pathways. Specifically, the 65% ethanol extract of Euphorbia hirta (EE65) and quercitrin (HPG) exerted anti-inflammatory activity by inhibiting the expression of inflammatory genes associated with the NF-κB signaling pathway, whereas baicalein (HCS) suppressed cellular inflammation by promoting Nrf2-mediated antioxidant gene expression and enhancing apoptosis of inflammatory cells. The results of the study suggest that Euphorbia hirta has potential for the development of anti-inflammatory drugs.