Artichoke leaf (Cynarae folium) 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. The liquid chromatography high-resolution tandem mass spectrometry (LC-HRMS/MS) metabolite profiling showed a complex composition, with phenolic acids (mostly mono- and 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 two extracts also displayed anti-enzymatic effects, as assessed in cholinesterase, tyrosinase, glucosidase and amylase tests. Lastly, the artichoke samples (at the concentration of 20 μg/mL) proved a very potent inhibition of the production of several pro-inflammatory cytokines, namely interleukin (IL)-1β [7.55–15.75% of lipopolysaccharide (LPS) + cells], IL-8 (11.72–13.46% of LPS + cells) and tumor necrosis factor (TNF)-α (4.07–10.35% LPS + cells), in LPS-stimulated human neutrophils. 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, anti-enzymatic and anti-inflammatory effects.