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Although the biochemical composition and biological properties of the volatile fraction of the halophyte sea fennel (<i>Crithmum maritimum</i> L.) have been largely described, little is known about its polar constituents and bioactivities. Here, a hydromethanolic extract of <i>Crithmum maritimum</i> (L.) leaves was fractionated, and the fractions were evaluated in vitro for antioxidant (using DPPH, ABTS, and FRAP bioassays), anti-inflammatory (inhibition of NO production in RAW 264.7 macrophages), antidiabetic (alpha-glucosidase inhibition), neuroprotective (inhibition of acetylcholinesterase), and skin-protective (tyrosinase and melanogenesis inhibitions) activities. Polar fractions of the extract were rich in phenolics and, correlatively, displayed a strong antioxidant power. Moreover, fractions eluted with MeOH₂₀ and MeOH₈₀ exhibited a marked inhibition of alpha-glucosidase (IC₅₀ = 0.02 and 0.04 mg/mL, respectively), MeOH₆₀ fractions showed a strong capacity to reduce NO production in macrophages (IC₅₀ = 6.4 μg/mL), and MeOH₈₀ and MeOH₁₀₀ fractions had strong anti-tyrosinase activities (630 mgKAE/gDW). NMR analyses revealed the predominance of chlorogenic acid in MeOH₂₀ fractions, 3,5-dicaffeoylquinic acid in MeOH₄₀ fractions, and 3-<i>O</i>-rutinoside, 3-<i>O</i>-glucoside, 3-<i>O</i>-galactoside, and 3-<i>O</i>-robinobioside derivatives of quercetin in MeOH₆₀ fractions. These compounds likely account for the strong antidiabetic, antioxidant, and anti-inflammatory properties of sea-fennel polar extract, respectively. Overall, our results make sea fennel a valuable source of medicinal or nutraceutical agents to prevent diabetes, inflammation processes, and oxidative damage.