The water and sediment exchange status between the middle reaches of Huaihe River and the Hongze Lake affects the intrinsic relationship between the river and lake. Based on the calculation of the water and sediment exchange indexes between Huaihe River and the Hongze Lake from 1975 to 2015, a variety of statistical tests were carried out for the trend variation, abrupt change test and periodic statistics analysis of the indexes. The results show that, affected by the Huaihe River regulation projects built in different ages, the water exchange between the river and lake generally showed an insignificant increasing trend, resulting in an insignificant increasing trend of the reservoir capacity of the Hongze Lake as well. Sediment into the lake was more than that out of the lake, and sediment deposition in the lake basin increased insignificantly year by year. However, the reservoir capacity and basin deposition of the Hongze Lake fluctuated stably during the study period, and there were no obvious abrupt changes. The water and sediment exchange degree between the Huaihe River and Hongze Lake showed multi-time scale periodic characteristics, with 14 a as the first principal period. The water and sediment exchange degree between the river and lake was in a relatively stable state. The research results clarified the water and sediment interactive relationship between the middle reaches of Huaihe River and the Hongze Lake, which could provide a theoretical guidance for river-lake governance.