Long an important regional center, Huai'an lies on and is named for the Huai River, the historical boundary between Northern and Southern Chinese culture.

Huai'an is known as the birthplace of Han Xin, a famed general who helped found the Han dynasty and overwhelm Xiang Yu in Chu-han contention; Wu Cheng'en (1500–1582), the Ming author of Journey to the West; and Zhou Enlai (1898–1976), a prominent and early Chinese Communist leader who served as premier of the PRC from 1949 until his death in 1976.

For much of the 20th century, Huai'an was officially known as Huaiyin in pinyin, Huai-yin in Wade-Giles, and Hwaiyin in Postal Map, all romanizing the Chinese name written 淮陰 in traditional characters and 淮阴 in simplified ones, meaning "area on the yin, shady, or south bank of the Huai".

Huai'an is situated almost directly south of Lianyungang, southeast of Suqian, northwest of Yancheng, and north of Yangzhou and Nanjing in Jiangsu and northeast of Chuzhou in Anhui.

In 486 BC, the hegemon Fuchai of Wu completed the Han or Hangou Canal (t 邗溝, s 邗沟, Hángōu), connecting his center of power at Suzhou near the Yangtze Delta with the Huai River at Huai'an to ease his supply lines in conflicts against Qi.

[clarification needed] During the Warring States period, the area was held in turn by Wu, Yue, and Chu before being conquered by Shi Huangdi of Qin.

In Jian'an 5 (c. 200), near the beginning of the Three Kingdoms period, the Guangling commander Chen Deng—then subordinate to Lü Bu—constructed the first 30-li section of the Gaojia Dike (高家堰, Gāojiāyàn) to minimize damage from flooding along the Huai.

[7] He also expanded the Hangou Canal westward and combined the small Fuling lakes into a single Pofu Pond to assist with irrigation.

Emperor Yang was also responsible for changing Pofu's name to the present-day Hongze Lake out of his delight at rainfall there, encountered after an inspection tour through drought-afflicted areas.

[8] During the Song, Kaifeng's governor Du Chong (杜充, Dù Chōng, d. 1141) breached the levees holding back the Yellow River in 1128 as part of the ongoing wars with the Jurchen Jin further north.

A series of massive floods, manmade and natural, then caused it to capture the Si River and begin flowing into the lower reaches of the Huai.

Now part of Huai'an, the area around it was administered as the separate Sizhou Prefecture during the Yuan, when it was the home of the family of the future Hongwu Emperor Zhu Yuanzhang.

Although his family moved to Fengyang in present-day Anhui before his birth, he erected a large mausoleum in honor of his grandfather, great-grandfather, and great-great-grandfather after his establishment of the Ming.

The area was occupied by the Japanese army during World War II and administered as part of Wang Jingwei's puppet regime.

At this time the Suwan (or Su-An) Border Region extended as far as the north bank of the Yangtze River, opposite the Republican capital, Nanjing.

[11] Presumably at some point, the city was recaptured by the Nationalists, because, during the closing phases of the Chinese Civil War, it fell to the Communist army in December 1948.

Currently the airport is served by China Eastern Airlines, which offers flights to Beijing-Capital, Chongqing, Guangzhou, Shanghai-Hongqiao, Shanghai-Pudong, Wenzhou, Wuhan, Xiamen, and Xi'an.