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While inflammation is a vital immune response to harmful stimuli, chronic inflammation has been associated with several diseases such as arthritis, cardiovascular disorders, and cancers. Plant extracts, rich in bioactive compounds, have been used in traditional medicine to manage inflammation by modulating inflammatory pathways. Specifically, Ziziphus nummularia (Sidr), known for its anti-inflammatory, antioxidant, and antimicrobial properties, contains flavonoids, saponins, triterpenoids, and phenolics, but its mechanisms of action remain unclear. This study investigated the anti-inflammatory effects of an ethanolic extract from Z. nummularia leaves (ZNE) in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. ZNE significantly reduced the expression of pro-inflammatory enzymes (COX2, iNOS), inhibited the production of inflammatory mediators (NO, ROS, TNF-α, IL-6), reduced cellular migration and modulated key signaling pathways (NF-κB, STAT-3, MAPKs). These findings highlight the potential of ZNE as a natural therapeutic agent for inflammation, warranting further exploration of its mechanism of action and potential clinical applications.