Background: Salsola imbricata Forssk. is a shrub widely growing in Egypt, used as a camel food, traditionally, used as anti‑inflammatory agent. Literature survey showed no report about the anti‑inflammatory activity of S. imbricata. Aim of the Study: This work was designed to study the phenolic constituents and to provide evidence for the traditional use of S. imbricata as an anti‑inflammatory agent. Materials and Methods: The in vitro anti‑inflammatory activity of the total aqueous methanol extract and some isolated compounds were investigated in RAW 264.7 macrophage cells using nitric oxide assay. All chemical structures were identified on the basis of electrospray ionization‑mass spectrometry, one‑ and two‑dimension nuclear magnetic resonance. Results: Nine phenolic compounds, among them two new natural products; isorhamnetin‑3‑O‑β‑D‑glucuronyl (1’’’→4’’) glucuronide (1) and its dimethyl ester; isorhamnetin‑3‑O‑β‑D‑di glucuronate dimethyl ester (2), two isorhamnetin glycosides: Isorhamnetin‑3‑O‑β‑D‑galactopyranoside (3), isorhamnetin‑3‑O‑β‑D‑glucopyranoside (4), and isorhamnetin (5). In addition, an alkaloidal phenolic; trans N‑feruloyl tyramine (6), three phenolic acids: Isovanillic acid (7), ferulic acid (8), and p‑hydroxy benzoic acid (9) were isolated from salsola imbricata leaves. All compounds were isolated and identified for the first time from this plant except compound (6). The extract and the tested compounds showed distintict anti‑inflammatory activities with no toxicity on RAW 264.7 macrophage cells. Conclusion: The extract and the tested compounds showed distintict anti‑inflammatory activities with no toxicity on RAW 264.7 macrophage cells.