Pacific white shrimp (Penaeus vannamei) is one of the main shrimp species cultivated around the world. Despite its high yields and easy handling, water pollution from intensive shrimp cultivation remains a serious problem in China. In this study, a compound aquaculture model of P. vannamei and water spinach (Ipomoea aquatica) was used to investigate the effect of a water spinach floating raft on water quality, antioxidants, non-specific immune response, growth performance, and microbial diversity. The experimental design of this study consisted of two groups with three replicates for each, i.e., control group: aquatic monoculture (AM) system with only P. vannamei; treatment group: P. vannamei-I. aquatica raft aquaponics (AP) system with a 50% cover ratio with a water spinach floating raft. The experiment lasted for seven weeks. The results show that the concentrations of total phosphorus (TP), total nitrogen (TN), nitrate nitrogen (NO3−-N), ammonia nitrogen (NH4+-N), nitrite nitrogen (NO2−-N), and active phosphorus (AP) in the AM group were higher than those in the AP group at different sampling times. The water quality index of the AP group was better than that of the AM group, indicating that water spinach can remove the nutrients from aquaculture water bodies. The average daily gain and survival rate of shrimp in the AP group were higher than those in the AM group. The total antioxidant capacity (T-AOC), catalase (CAT), superoxide dismutase (SOD), malondialdehyde (MDA), and acid phosphatase (ACP) in the AP group were better than those in the AM group. The Shannon–Wiener and Simpson indices of the gut, water, and sediment of the AP system were significantly higher than those in the AM system, which implied a higher abundance of microorganisms in the AP system. These results demonstrate that the application of a water spinach floating raft in aquaponics can not only improve the water quality, but also improve the growth performance, antioxidant system, and non-specific immune responses of Pacific white shrimp, while increasing the abundance of microorganisms in the aquaculture system and improving the ecological benefits in terms of the expenditure.