Swine wastewater (SW) treatment by Myriophyllum aquaticum is an important biotechnology for its resource utilization. However, some knowledge gaps remain in compound-pollutant removal in SW, especially in practical applications. To clarify the responses of M. aquaticum to the compound pollutants as well as the related operational parameters in SW treatment, three initial doses (0.5, 1.0, and 1.5 kg per pond in 150 L simulated SW) of M. aquaticum and a control (no plant; CK) were allocated to 12 ponds under a plastic roof in Nanjing city of Eastern China during 75 days in the summer of 2019. Results showed that M. aquaticum could be used as a pioneer plant to efficiently remove compounded pollutants of nitrogen (N), phosphorus (P), and especially for heavy metals in simulated SW. Compared with CK, M. aquaticum assisted in improving the total N, NH₄⁺–N, NO₃^-–N, NO₂^-–N, and dissolved organic N by 30.1%, 100%, 100%, 97.6%, 20.2%, 39.8% whereas Cu, Zn, and Cd by 50.4%, 36.4% and 47.9% on average during the 75-day experiment in summer, respectively. Moreover, concentrations of Cu and Cd at day 75 were in the ranges of 1.92–2.82 and 0.64–1.47 g kg⁻¹ DW, respectively, exceeding the corresponding limits of the heavy-metal hyperaccumulator. For the operational parameters, the optimized initial dose was 1.0 kg per pond with M. aquaticum harvested after 45 summer days, respectively. Given that M. aquaticum has been widely used as animal feed in recent years and limit values for Cu and Zn in animal feed are not set in China, the toxicities of Cu and Zn should be assessed and the guideline of their limit values needs to be established for safe feed production. Interestingly, NH₄⁺–N could dominate the removal of heavy metals especially Cd in the simulated SW, however, related mechanisms are needed for further study.