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In this study, the compound aquaculture model of red tilapia (O. mossambicus albina × O. urolepis hornorum) and water spinach (Ipomoea aquatica) was used to investigate the effect of water spinach rafts on the water quality, antioxidant system, non-specific immune response, and growth performance of red tilapia and the carbon balance of payments. Red tilapia is characterized by its high adaptability to different production environments and food sources, as one of the most productive fish in aquaculture, and is well accepted in the market due to its nutritional and organoleptic characteristics. The experiment lasted for nine weeks and included two systems: the red tilapia-water spinach raft aquaponics (AP) system with 10% cover ratio with water spinach floating beds, and the aquatic monoculture (AM) system with only red tilapia. The total phosphorus (TP), total nitrogen (TN), and nitrate nitrogen (NO−3-N) in the AM were higher than those in AP from the fifth to ninth week. On the second, third, fifth, and sixth weeks, the ammonia nitrogen (NH4+-N), in the AM was higher than those in the AP. From the seventh week, the pH of the AM was significantly lower than the AP, while the nitrite nitrogen (NO−2-N) was significantly higher than the AP. The water quality index of the AP was better than that of the AM, indicating that water spinach can remove the nutrients from aquaculture water bodies. The average daily gain and specific growth rate (SGR) of fish in AP were higher than those in the AM. The acid phosphatase (ACP), alkaline phosphatase (AKP), and catalase (CAT) activities in the hepatopancreas of red tilapia in the AP were also significantly higher than those in the AM, while the malondialdehyde (MDA) in the AP was lower than the AM. The serum ACP and CAT of red tilapia in the AP were also higher than those in the AM, while the MDA of fish in the AP was lower than the AM. The results showed that both the experimental group and the control group were carbon sources and released greenhouse gases into the atmosphere, but the total carbon emissions of the red tilapia and the water spinach symbiotic system in the experimental group was significantly lower than that of the control group (p < 0.05). These results demonstrated that the application of water spinach rafts in aquaponics can not only improve the water quality, but also improve the growth performance, antioxidant system and non-specific immune responses of red tilapia, while promoting the utilization of organic matter in the aquaculture system, improving the ecological benefits in terms of the carbon income and expenditure. [ABSTRACT FROM AUTHOR]