Aim: Artichoke leaf extracts are used as traditional herbal medicinal products to treat a wide range of human ailments, being widely commercialized as nutraceutical or pharmaceutical preparations. In the current study, the hydromethanolic dried leaf extracts of Cynara scolymus L. var. major Brotero and C. scolymus L. var. redonensis N.H.F. Desp. were phytochemically and biologically investigated. Methodology: The phytochemical characterization of artichoke leaf extracts was assessed by liquid chromatography hyphenated with tandem high-resolution mass spectrometry (LC-HRMS/MS) analysis. The biological profile screening was achieved by in vitro testing of their antioxidant effects (free radical scavenging, metal chelating and reducing power, total antioxidant capacity) and by ex vivo testing of their ability to inhibit the release of pro-inflammatory cytokines [interleukin (IL)-1β, IL-8 and tumor necrosis factor (TNF)- α] from lipopolysaccharide (LPS)-stimulated human neutrophils. Results: LC-HRMS/MS metabolite profiling showed a complex composition, with phenolic acids (mostly monoand di-caffeoylquinic acids), flavonoids and sesquiterpene lactones as the most representative classes. The strong antioxidant activity of the two C. scolymus varieties was evidenced in DPPH [64.84-65.21 mg trolox equivalents (TE)/g] and ABTS (86.39-95.55 mg TE/g) radical scavenging, cupric (160.49-171.07 mg TE/g) and ferric (71.47-78.95 mg TE/g) reducing capacity, metal chelating and phosphomolybdenum assays. In addition, the artichoke samples (at the concentration of 20 μg/mL) proved a very potent inhibition of the production of several pro-inflammatory cytokines, namely IL-1β (7.55-15.75% of LPS+ cells), IL-8 (11.72-13.46% of LPS+ cells) and TNF-α (4.07-10.35% LPS+ cells), in LPS-stimulated human neutrophils. Conclusions: Overall, the results of our study indicate that the two C. scolymus varieties could be regarded as a rich source of biologically active compounds, opening thus the perspectives for their future large-scale cultivation and valorization as bio-functional ingredients with putative antioxidant and anti-inflammatory effects.