Decoupled aquaponic systems have the potential to become one of the most effective sustainable production systems for the combined production of animal protein and plant crops. Here, recirculating aquaculture systems for fish production are combined with hydroponics for soilless plant production thereby recycling dissolved nutrients derived from metabolism of the fish. The aim of the present study was to characterize hydroponic lettuce production using conventional nutrient solution in comparison with decoupled aquaponics using the nutrient rich fish water as basis for the nutrient solution being supplemented by missing nutrients. In addition, one aquaponic treatment became disinfected in order to assess any occurring advantage of the aquaponics derived fish water. For evaluation the temperature, electrical conductivity, pH, and the mineral composition of the nutrient solution, as well as colony forming units in the fish water were monitored. Additionally, plant growth (fresh and dry weight, number and area of leaves) and quality parameters of lettuce leaves (nitrate, mineral content, phenolic compounds) were examined. Carbon sources and microorganisms derived from fish water seem to have neither beneficial nor detrimental effects on plant growth in this study. Except for some differences in the mineral content of the lettuce leaves, all other quality parameters were not significantly different. The use of aquaponic fish water saved 62.8% mineral fertilizer and fully substituted the required water for the nutrient solution in comparison to the control. Additionally, the reduced fertilizer demand using decoupled aquaponics can contribute to reduce greenhouse gas emissions of an annual lettuce production site per ha by 72% due to saving the energy for fertilizer production. This study clearly demonstrates the huge potential of the innovative approach of decoupled aquaponics to foster the transformation of our conventional agriculture towards sustainable production systems saving resources and minimizing emissions.