Floods caused by extreme precipitation events, in the context of climate warming, are one of the most serious natural disasters in monsoon region societies. The great flood in the Yangtze River Basin in 1849, in Eastern China, was a typical extreme flood event. According to historical archives, local chronicles, diaries, and historical hydrological survey data, this study reconstructed the temporal and spatial patterns of extreme precipitation in 1849, and the flood process of the Yangtze River. We found four major precipitation events at the middle and lower reaches of the Yangtze River, from 18 May to 18 July 1849. The torrential rainfall area showed a dumbbell-like structure along the Yangtze River, with two centers distributed separately in the east and west. For the specific flood process of the Yangtze River, many tributaries of the Yangtze River system entered the flood season consecutively since April, and the mainstream of the Yangtze River experienced tremendous pressure on flood prevention with the arrival of multiple rounds of heavy rainfall. In mid-to-late July, the water level and flow rate of many stations along the mainstream and tributaries had reached their record high. The record-breaking peak flow rate at many stations along the mainstream and tributaries in the middle reaches of the Yangtze River indicated intense precipitation in the area. The heavy rainfall disaster in the Yangtze River Basin could be driven by these reasons. First, the cold air in North China was extraordinary active in 1849, which made it difficult for the subtropical high pressure to move northward. Second, the rain belt stagnated in the Yangtze River Basin for a long time, and the Meiyu period reached 42 days, 62% longer than normal years. Third, the onset of a southwest monsoon was earlier and more active, which provided abundant moisture to the Yangtze River Basin. The great flood disaster was caused by heavy precipitation at the middle reaches, which made it quite different from the other three great floods in the Yangtze River in the 20th century. At present, the large water conservancy projects in the Yangtze River are mainly designed for flood problems caused by rainstorms in the upper reaches of the Yangtze River. The middle reaches of the Yangtze River, however, are facing the weakening of flood diversion capacity, caused by social and economic development. Therefore, future flood prevention measures in the Yangtze River should pay great attention to the threat of this flood pattern.