Abstract: Arjunic acid (AR), a main bioactive triterpenoid isolated from acorns, has been reported to exert pronounced anti-inflammatory activities. However, its anti-inflammatory mechanisms have not been elucidated. In this study, the model of lipopolysaccharide (LPS)-induced inflammation in RAW264.7 cells were established to investigate the anti-inflammatory activity of AR. The potent targets and signaling pathway of AR for the treatment of inflammation-related disease were predicted based on network pharmacology. Furthermore, the expression of pro-inflammatory cytokines and mediators was determined by Griess assay, enzyme-linked immunosorbent assay (ELISA), qRT-PCR, and Western blot. The protein expression of NF-κB, MAPK, Nrf2/HO-1, PI3K/Akt/mTOR, and autophagy signaling pathways were gauged by Western blot. As the result, in the inflammatory model of LPS-induced RAW264.7 cells, AR could significantly inhibit the expression of pro-inflammatory cytokines and mediators, suppress the phosphorylation and translocation of NF-κB, and downregulate the phosphorylation of JNK/ERK signaling pathways. AR also inhibited ROS production and activated the Nrf2/HO-1 signaling pathway by degrading Keap1. Furthermore, AR activated autophagic flux by inhibiting the PI3K/Akt/mTOR signaling pathway. Collectively, AR was a potential natural product for the treatment of inflammation-related diseases.