Soil enzymes are an important part of a wetland ecosystem. In this study, we evaluated the responses of soil enzymatic activities to long-term warming in relation to soil carbon, nitrogen, and phosphorus; this model has an important meaning in Yangtze Estuary Wetlands with Phragmites australis sustainable management under the conditions of climate warming. An in situ simulated warming experiment was conducted on the Eastern Chongming wetland with P. australis in the Yangtze Estuary; open-top chambers (OTCs) were applied to simulate climate warming. In the eighth year of warming, we studied the responses of several important soil enzymatic activities (invertase, urease, acid phosphatase, neutral phosphatase, and alkaline phosphatase) to long-term warming at soil depths of 0-10 and 10-20 cm. After eight years of continuous warming, the simulated warming signifcantly increased soil enzymatic activities at soil depths of 0-20 cm. The activities of invertase, urease, acid phosphatase, neutral phosphatase, and alkaline phosphatase increased by 71.9%, 84.7%, 41.8%, 105.7%, and 18.9%, respectively, at soil depths of 0-10 cm and increased by 38.0%, 92.6%, 46.2%, 87.7%, 34.0%, respectively, at soil depths of 10-20 cm. The effects of interaction of the warming, season, and soil depth on soil enzymatic activities were signifcant. The long-term simulated warming signifcantly improved spring (April) invertase activity at the 0-10 cm soil depth but signifcantly reduced soil acid phosphatase, neutral phosphatase, and alkaline phosphatase activities. The simulated warming signifcantly increased soil invertase, urease, and neutral phosphatase activities in the summer (July) at soil depths of 0-20 cm. In the autumn (October), fve soil enzymatic activities also signifcantly increased at two depths, but the long-term warming had no signifcant effect on fve soil enzymatic activities in winter (December). Correlation analysis revealed that invertase and neutral phosphatase activities signifcantly positively correlated with soil temperature; the activities of fve soil enzymes showed a signifcant positive correlation with soil organic carbon content; and invertase, acid phosphatase, and alkaline phosphatase activities signifcantly positively correlated with soil total phosphorus content. The long-term simulated warming signifcantly changed soil enzymatic activities; this alteration could have important effects on nutrient cycling in reed wetlands on Eastern Chongming Island in the Yangtze Estuary.