The risk of famine and food insecurity in the process of socioeconomic development is an important issue. This study examined the trend of famines in the Jiangsu and Shanghai region in the Qing Dynasty during 1644-1911. Based on the 1487 famine records extracted from local chronicles and other historical materials, this study first reconstructed two annual sequences of famines (frequency of counties affected by famine and its weighted index) by using the semantic differential method and weighted index. Then, the study quantitatively explored the spatial-temporal variations of the famines and their causes from different factors and their combinations during the Qing Dynasty, using multiple statistical tools such as wavelet analysis and kernel density estimation. The results show that: 1) Famines were very frequent in the Jiangsu and Shanghai area throughout the Qing Dynasty, with an average of one famine per 1.2 years and six counties affected annually by famines, but the vast majority of famine years were dominated by mild famines (grade 1) and moderate famines (grade 2). The frequency and intensity of the famines in the study area displayed clear patterns of phasic, periodic, seasonal, and intermittent explosive changes. The most serious periods were the mid-late part of the prosperous Kangxi-Qianlong times, and the periods during the reigns of Daoguang and Xianfeng when the Qing Dynasty turned from prosperity to decline. In addition to the increasing frequency of extreme droughts and floods in these two periods, it might also be related to the significant increase in the exposure and vulnerability of the social system to disasters and famines at those times. 2) The spatial distribution of famines is characterized by a pattern of "two-zones and multi-nucleus" from southeast to northwest. The areas along the banks of the Yangtze River, around the Taihu Lake and the Gaoyou Lake, the old Yellow River course and the Hongze Lake were famine-prone areas. Besides the social factors like population and economic development, the geographic environment, especially the distribution of water bodies, had an important impact on the distribution of famine-prone areas. 3) The main environmental factors that caused famine were flooding, followed by droughts and storm surges, and other disasters accounted for only a small part. The combination of different disaster-causing factors would have different effects on famine. The proportion of famines caused by a single environmental factor accounted for the vast majority. With regard to the severity of famine, the mean famine index values corresponding to those caused by a combination of two and three environmental factors were both larger than that of a single factor. The distribution of famines related to floods and droughts determined the overall distribution pattern of famines in the Jiangsu-Shanghai region during 1644-1911. The above understanding can provide some valuable reference for identifying high-risk areas of famine in Jiangsu and Shanghai and exploring the impact of regional natural hazards on famine and protection mechanisms of food security in the future.