Sediment nutrient levels and water-level fluctuations are important factors that affect the development and growth of submerged macrophytes; however, little is known about the adaptive responses of macrophytes to these factors. We conducted an experiment using the submerged macrophyte Myriophyllum spicatum L. grown under 2 sediment nutrient levels (high: 2.7 mg g −1 total nitrogen, TN; 1.5 mg g −1 total phosphorus, TP; low: 1.45 mg g −1 TN and 0.70 mg g −1 TP) and 3 amplitudes of water-level fluctuation (static, ± 50 cm, ±100 cm) in outdoor ponds. We hypothesized that increased nutrient supply would promote the growth of M. spicatum, which can acclimate to the negative effects of moderate water-level fluctuations. After 112 d of growth under high-nutrient conditions, the plants produced a greater shoot biomass (higher branch number and length), resulting in greater accumulation of total biomass. However, plant growth was inhibited by increasing the amplitude of the water-level fluctuations: at ±100 cm, the plants allocated more biomass to the roots and produced fewer and longer branches. Conversely, plant growth was promoted in the high-nutrient sediments at ± 50 cm amplitude. The production of auto-fragments was increased in the high-nutrient sediment but was significantly decreased by high water-level fluctuations. Thus, sediment nutrient levels and water-level fluctuations have strong interactive effects on the growth and reproduction of M. spicatum, and increased sediment nutrients in combination with moderate water level fluctuations facilitate nutrient acquisition, plant growth, and reproduction. Our study implies that moderate water-level fluctuations benefit the restoration of submerged macrophyte communities, particularly in high-nutrient habitats.