This study aimed to investigate the chemical constituents and in vitro pharmacological activity (antioxidant, antimicrobial, anti-inflammatory and cytotoxic activity) of the ethyl acetate (EtOAc) and methanol (MeOH) extracts of Salsola kali aerial parts. EtOAc extract showed potent activity against all tested pharmacological studies better than MeOH extract. It exhibited potent antioxidant activity for three tested mechanisms where, the total antioxidant capacities (TAC) were 873.27 and 302.5 mg AAE/g extract, reducing power was 223.62±3.46 & 213.02±1.99 mg AAE/g extract and DPPH scavenging activity with an IC50 of 41.52±2.09 and 80.64±4.53 µg/ml for EtOAc and MeOH extracts of S. kali, respectively. EtOAc and MeOH extracts displayed moderate to weak antibacterial activity against tested strains. EtOAc extract revealed the highest membrane stabilizing activity with IC50 of 1.68 mg/mL whereas, MeOH extract exhibited membrane stabilizing activity with IC50 of 2.60 mg/mL as compared to the drug reference. EtOAc extract showed potent cytotoxic activity against HepG2, A549 and MCF-7 with IC50 24.7, 29.3, and 44.0 μg/mL respectively, while the MeOH extract showed slight activity against the three tested cell lines with IC50 between 180-291μg/mL. For the first time, salisoflavan, syringic acid, and tricin-7-O-glucopyranoside were isolated from this plant. LC-MS analysis of the EtOAc extract of S. kali led to the identification of 127 phytoconstituents.