L. is a spontaneous halophytic plant, widespread in coastal environments, recognized for its high polyphenol content and bioactivities. In this study, a sustainable extraction strategy was developed by coupling natural deep eutectic solvents (NADESs) with ultrasound-assisted extraction (UAE) to recover bioactive compounds from autochthonous collected in the Apulia region of southern Italy. Sixty-one NADES combinations were screened using COSMOtherm software, based on the predicted solubility of isorhamnetin, the major flavonol in spp, to identify optimal hydrogen-bond donor (HBD) and acceptor (HBA) pairs. Six selected and prepared NADESs (B:CA, B:Suc, ChCl:U, ChCl:Xil, CA:Glc and Pro:MA) were used to extract , and the resulting extracts were evaluated for total phenolic content (TPC), antioxidant capacity (DPPH, ABTS, FRAP) and antibacterial activity against four ATCC bacterial strains (, , and ). Among the tested extracts, Pro:MA exhibited the highest TPC (6.79 mg GAE/g) and interesting antioxidant activity (DPPH IC = 0.09 mg GAE/g; ABTS = 8.12 mg TE/g; FRAP = 2.41 mg TE/g). In the antibacterial assays, the Pro:MA extract demonstrated the highest activity, with minimum inhibitory concentrations (MICs) ranging from 0.1% to 0.4% / and minimum bactericidal concentrations (MBCs) from 0.2% to 0.8% /. In addition, the Pro:MA extract maintained TPC stability over a 90-day storage period. These findings support the NADES-UAE system as a green and efficient approach for the recovery of bioactive compounds and for the valorization of halophyte plants, such as , with promising ready-to-use applications in the food, pharmaceutical and cosmeceutical sectors.