This work aimed to investigate the richness of a Tunisian xerohalophyte Frankenia thymifolia aerial and root parts on phenolics and to evaluate the antioxidant and neuroprotective properties of this medicinal species. After fractionation using increasing and different solvent polarities, results displayed five fractions, where ethyl acetate (EtOAc) shoot and root fractions possess considerable total phenolic contents (221 and 308 mg of GAE/g of E, resp.) related to their important antioxidant activities such as ORAC (918 and 713 mg of TE/g of E), DPPH (282 and 821 mg of TE/g), and ABTS (778 and 1320 mg of TE/g) tests. Then, the identification of the main compounds by HPLC-DAD-ESI-MS and neuroprotective property of the most active fraction EtOAc were assessed. A total of 14 molecules were identified, which have been described for the first time in F. thymifolia. The major compounds identified were pinoresinol and kaempferol glycoside in aerial parts and gallic acid and ellagitannin in roots. Neuroprotective capacity against β-amyloid (Aβ) peptide induced toxicity in PC12 cells of EtOAc fraction showed a significant protective activity at lower concentration (25 and 50 µM). The relevant antioxidant and neuroprotective activities of F. thymifolia EtOAc fraction corroborated their chemical compositions.