The employment of traditional bait and medicament in freshwater aquaculture causes the frequent occurrence of environmental pollution and disease. Effluent collected after wastewater treatment with Rhodopseudomonas sphaeroides could be reutilized for microbial feed, medicament, and aquaculture water to culture Common Carp Cyprinus carpio. Therefore, a novel integrated system of wastewater treatment and the use of the effluent containing R. sphaeroides, which could improve yield, increase disease resistance, and enhance the quality of aquaculture water for Common Carp culture, was proposed and investigated. Common Carp can grow well in effluent containing R. sphaeroides. The survival rate, yield, and whole‐body composition of the fish raised in effluent containing R. sphaeroides were all increased compared with the control group. The biochemical (B vitamin) and other substances in the effluent with R. sphaeroides enhanced the activity of proteases, amylases, lipases, alkaline phosphatase, acid phosphatase, phagocytes, superoxide dismutase, and catalase by up‐regulating the expression of their associated genes. Theoretical analysis showed that biochemical molecules regulate the expression of these gene and enzyme activities by acting as a signal that stimulates the active center. Moreover, biochemicals present in R. sphaeroides enhanced the mTOR and NF‐kB signaling pathways and improved intestinal microbiota. Furthermore, R. sphaeroides inhibited Aeromonas hydrophila, increasing resistance against fish disease and promoting the growth of intestinal bacteria. Meanwhile, R. sphaeroides in the effluent also improved the aquaculture water quality. This technology would simultaneously save water in aquaculture, reduce water pollution and wastewater discharge, and increase the output and disease resistance of Common Carp.