A sustainable alternative to replace the use of toxic and non-biodegradable conventional solvents for the extraction of active principles from plants is natural deep eutectic solvents (NADESs). Cav. (Zygophyllaceae) is a plant widely distributed in semiarid areas of western Argentina. Several studies validate its popular medicinal use by demonstrating its biological activities such as antibacterial, antifungal, antioxidant, anti-inflammatory, and anticarcinogenic properties, among others. The aim of this work was to compare the bioactive compounds and the in vitro antioxidant and antibacterial activity of extracts using non-conventional vs. conventional solvents. Aqueous, ethanolic, and four NADES extracts were prepared. The extracts were phytochemically characterized, and extracted compounds were identified by UHPLC-MS/MS. Antioxidant activity was determined by evaluating the hydrogen peroxide and free radical scavenging capacity using ABTS. The antibacterial activity of the extracts and NADESs was evaluated against Gram-positive and Gram-negative multidrug-resistant strains. The extracts of presented a variable content of total phenolic compounds between 4163.4 and 24,371.63 µg GAE/mL. Phenolic acids, flavonoid glycosides, flavanones, flavones, flavonols, alkaloids, lignans (nordihydroguaiaretic acid and its derivatives), and other compounds were tentatively identified in extracts of obtained with conventional and non-conventional solvents. A heatmap cluster and a bubble plot were created to compare the diversity and relative abundance of identified compounds, and the extracts were classified into two major groups. All extracts were able to scavenge > 40% of hydrogen peroxide and the ABTS radical cation (ABTS) (CD = 3.15-5.13 µg GAE/mL). The LAS extract exhibited the highest bacterial growth inhibition (MIC = 75-37.5 µg GAE/mL). In conclusion, the results show that NADESs represent a sustainable alternative for the extraction of compounds with antioxidant and antibacterial activity and could therefore replace traditional solvents in the pharmaceutical, cosmetic, or food industries.