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Due to its rising antibiotic resistance and associated inflammations, <i>Helicobacter pylori</i> poses a challenge in modern medicine. <i>Salvia officinalis</i>, a member of the Lamiaceae family, is a promising medicinal herb. In this regard, a phytochemical screening followed by GC-MS and LC-MS was done to evaluate the chemical profile of the total ethanolic extract (TES) and the essential oil, respectively. The anti-<i>H. pylori</i> and the anti-inflammatory activities were evaluated by a micro-well dilution technique and COX-2 inhibition assay. Potential anti-<i>H. pylori</i> inhibitors were determined by an in silico study. The results revealed that the main metabolites were flavonoids, sterols, volatile oil, saponins, and carbohydrates. The LC-MS negative ionization mode demonstrated 12 compounds, while GC-MS showed 21 compounds. Carnosic acid (37.66%), epirosmanol (20.65%), carnosol1 (3.3%), and 12-<i>O</i>-methyl carnosol (6.15%) were predominated, while eucalyptol (50.04%) and camphor (17.75%) were dominant in LC-MS and GC-MS, respectively. TES exhibited the strongest anti-<i>H. pylori</i> activity (3.9 µg/mL) asymptotic to clarithromycin (0.43 µg/mL), followed by the oil (15.63 µg/mL). Carnosic acid has the best-fitting energy to inhibit <i>H. pylori</i> (−46.6769 Kcal/mol). TES showed the highest reduction in Cox-2 expression approaching celecoxib with IC₅₀ = 1.7 ± 0.27 µg/mL, followed by the oil with IC₅₀ = 5.3 ± 0.62 µg/mL. Our findings suggest that <i>S. officinalis</i> metabolites with anti-inflammatory capabilities could be useful in <i>H. pylori</i> management. Further in vivo studies are required to evaluate and assess its promising activity.