As a green aquaculture model, aquaponic systems have considerable potential for improving the aquaculture environment, but their effects on produced animals remain insufficiently understood. In this study, a Houttuynia cordata-based decoupled aquaponic system was established for Nile tilapia production. Its effects on the aquaculture water environment and physiological status of Nile tilapia were evaluated through water quality monitoring, serum biochemical analysis, hepatic antioxidant assessment, and brain stress-related gene expression. The system reduced ammonia nitrogen, nitrite nitrogen, total phosphorus, permanganate index, and suspended solids, while reductions in total nitrogen and sulfide occurred only at specific time points. The system also improved hepatic function, lipid metabolism, and renal function. Notably, hepatic CAT, SOD, and GSH-Px activities increased, indicating enhanced enzymatic antioxidant defense. In brain tissue, gad2 and penk were upregulated, whereas comtb and pnmt were downregulated, suggesting altered neural regulation and stress-related responses. Overall, the Houttuynia cordata-based decoupled aquaponic system improved the aquaculture water environment and multiple aspects of Nile tilapia physiology, particularly hepatic enzymatic antioxidant defense, while modulating neural- and stress-related responses.