The extraction of valuable phytochemicals from natural sources is an important and constantly evolving research area. Zingiber officinale Roscoe (ginger) contains high amounts of bioactive phytochemicals, which are desirable due to their significant properties. In this work, the ability of different natural deep eutectic solvents (NaDESs) to serve as green solvents for the preparation of high added value extracts from ginger is explored, in combination with ultrasound assisted extraction. The method was optimized by applying a response surface methodology using the NaDES Bet/La/W (1:2:2.5). Three independent variables, namely the extraction time, ultrasound power and NaDES-to-dry-ginger ratio, were investigated by employing a 17-run three-level Box–Behnken Design (BBD) in order to study the correlation between the extraction conditions and the quality of the obtained extracts. The optimum conditions (in order to achieve simultaneously maximum total phenolic content and antioxidant activity), were found to be 23.8 min extraction time, 60 Watt and NaDES/ginger 25:1 w/w. In the optimum conditions the DPPH radical scavenging ability of the extracts was found to reach IC₅₀ = 18.16 mg/mL after 120 min, whereas the TPC was 20.10 ± 0.26 mg GAE/g of dry ginger. The green methodology was also compared with the extraction using conventional solvents. All the obtained extracts were evaluated for their antioxidant activity and their total phenolic content, while the extract derived by the optimum extraction conditions was further investigated for its ability to bind to calf thymus DNA (ctDNA).