Although the biochemical composition and biological properties of the volatile fraction of the halophyte sea fennel (Crithmum maritimum L.) have been largely described, little is known about its polar constituents and bioactivities. Here, a hydromethanolic extract of Crithmum maritimum (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-O-rutinoside, 3-O-glucoside, 3-O-galactoside, and 3-O-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.