Background: Acne vulgaris (AV) is a common adolescent skin condition which is mainly caused by Cutibacterium acnes overcolonization and subsequent inflammation. Objective: Our previous studies demonstrated that ethanol extracts of Meconopsis quintuplinervia Regel (EMQ) possess significant antimicrobial properties. However, their protective effects and potential mechanisms against AV remain unclear. Methods: In the present study, the EMQ treatment potential for AV was evaluated in a C.acnes-induced mouse ear edema model, and the EMQ anti-inflammatory mechanism was evaluated in lipopolysaccharide (LPS)-induced RAW264.7 macrophage cells. Results: The results showed that EMQ alleviated edema formation and inflammatory cell infiltration in an acne mouse model by suppressing inflammatory cytokines interleukin (IL)-6, IL-1β, and tumor necrosis factor α expression. Moreover, EMQ inhibited the phosphorylation of MAP kinases (MAPKs) such as p38, JNK, and ERK, the phosphorylation and degradation of IκB-α and the nuclear translocation of nuclear factor kappa B (NF-κB) p65 in LPS-induced RAW264.7 cells. Conclusion These findings suggest the potent anti-inflammatory activity of EMQ is possibly through the regulation of the MAPKs and NF-κB signaling pathways. Inhibition of C. acnes activity combined with a powerful anti-inflammatory effect of EMQ indicated its potential as a novel therapeutic option for AV.