Huai'an is a renowned historical and cultural city in China. Traces of human activity date back as early as 6,000 years ago, and the city is noted for the Qingliangang Culture recorded in history. During the Xia, Shang, and Zhou dynasties, the area was known as a settlement for the "Huaiyi" and "Xuyi" tribes. During the Spring and Autumn Period and the Warring States Period, not only was the Han Canal (also known as the Huaiyang Canal) constructed by King Fuchai of Wu to connect the Yangtze River and the Huaihe River, but there was also a crucial land route known as Shandao that facilitated travel and trade between the north and south. The Preface to the Chronology of the Huai River System states that the middle and lower reaches of the ancient Huaihe River, along with its surrounding areas, ranked first in terms of transportation and irrigation across the country, making it a key region for which various vassal states competed. The area was successively controlled by the Wu, Yue, and Chu states. After unifying the six states, the Qin dynasty implemented a system of prefectures and counties. The city falls under the jurisdiction of Sishui Prefecture and Donghai Prefecture, encompassing Huaiyin (Matou Town in today's Huaiyin District), Xuyi (northeast of today's Xuyi County), and Dongyang (southeast of Maba Town in today's Xuyi County). During the Western Han Dynasty, the city was primarily under the jurisdiction of Linhuai Prefecture, and the counties of Huaipu (west of present-day Lianshui County), Sheyang (southeast of what is now Huai'an District), and Fuling (the area of today's Hongze Lake) were incorporated. During the Eastern Han Dynasty, the city was divided between Xiapi State and Guangling Prefecture.

During the Wei, Jin, and Southern and Northern Dynasties, the city frequently found itself at the forefront of wars and conflicts, leading to chaotic administrative divisions and shifting allegiances. Presently known as Matou Town and Huaicheng Town within the urban area, these locations served as military fortresses back then, hosting state and prefecture governments, along with stationed border marshals. The years of chaos brought about by the war resulted in a miserable scene between the Yangtze River and Huaihe River, with thousands of miles of barren land, and caused significant economic and cultural damage. In the seventh year of Yongming during the Southern Qi Dynasty (489), 100 households of homeless and miscellaneous people from Huaiyin Town were relocated to the area east of Zhidu County and Pofu Pond, which was then designated as Huai'an County. This marked the first appearance of the name "Huai'an."

During the Sui, Tang, and Five Dynasties period, the region enjoyed a long-lasting stable environment, with a relatively stable administrative structure. Northern Huai'an generally fell under the jurisdiction of Sizhou (on the opposite bank of the Huaihe River, north of present-day Xuyi County), while southern Huai'an was part of Chuzhou (what is now Huaicheng Town in the Huai'an District). This stable environment allowed the economy to develop continuously and prosper once more. Chuzhou and Sizhou became two nationally renowned cities along the canal, with Chuzhou being praised as "the first prefecture southeast of the Huaihe River" by Bai Juyi. During the Northern Song Dynasty, the region experienced a period of relative peace. Initially, the city was part of Huainan Circuit, specifically within the jurisdictions of Chuzhou and Sizhou. Later on, Huainan Circuit was divided into Huainan East Circuit and Huainan West Circuit, with the city becoming part of Huainan East Circuit. During the conflicts between the Southern Song Dynasty and the Jin and Yuan dynasties, the city once again transformed into a front line, repeatedly contested by both sides. The administrative structure in the area became complex and changeable. During the Yuan Dynasty, the Huaidong Pacification Commission, the Huaidong General Administration Office, and the Huai'an Circuit (now Huaicheng Town in the Huai'an District) were successively established. The jurisdiction of Huai'an Circuit encompassed the majority of northern Jiangsu and portions of northern Anhui. During the Ming and Qing dynasties, Huai'an Prefecture was established. In the Ming Dynasty, Huai'an Prefecture governed nine counties and two prefectures, including Shanyang, Qinghe, Andong, Yancheng, Taoyuan, Suqian, Shuyang, Suining, Ganyu, Pizhou, and Haizhou. This area encompassed most of what are now five cities in northern Jiangsu. During this period, the Director-general of Grain Transport and the Viceroy of Southern Rivers were stationed in Huai'an. The Director-general of Grain Transport often simultaneously served as the Jianghuai Governor, overseeing four prefectures: Huai'an, Yangzhou, Luzhou, and Fengyang, as well as Xuzhou, Chuzhou, and Hezhou. The jurisdiction spanned the extensive region north of the Yangtze River in what are now Jiangsu and Anhui provinces. At the end of the Qing Dynasty, Jianghuai Province was temporarily established. Huai'an served as the location where the Jianghuai Governor was stationed, effectively making it the provincial capital.

In the first year of the Republic of China (1912), Huai'an Prefecture was abolished, and most of the city was incorporated into Huaiyang Circuit (with the administrative office located in present-day Qingjiangpu District). It was later assigned to the Huaiyin Administrative Supervision Zone and the Seventh Administrative Supervision Zone. During the War of Resistance Against Japanese Aggression and the War of Liberation, Huai'an emerged as a significant anti-Japanese democratic base area and a key liberated area. It served as the temporary headquarters for several major organizations, including the Central China Bureau of the CPC Central Committee, the New Fourth Army Headquarters, the Central China Branch of the CPC Central Committee, the Central China Military Area Command, and the Jiangsu-Anhui Border Region Government. Due to its location behind enemy lines, the administrative divisions of the base and liberated area underwent significant changes. It generally fell under the districts of Huaihai, Yanfu, Huainan, and Huaibei, respectively. From the victory of the War of Resistance Against Japan until September 1946, Huai'an served as the center of the Central China Liberated Area and the capital of the Jiangsu-Anhui Border Region. At that time, the Jiangsu-Anhui Border Region was delineated by the Yangtze River to the south, the Longhai Railway to the north, the Yellow Sea to the east, and Yuxikou to the west. It spanned across four provinces: Jiangsu, Anhui, Henan, and Shandong, encompassing 53 former counties under its jurisdiction. In December 1948, the entire city was liberated. In May 1949, the Huaiyin Special District was established.

After the founding of the People's Republic of China, the Huaiyin Special District was initially part of the Northern Jiangsu Administrative Region and later became part of Jiangsu Province. After the zoning adjustments in June 1950, August 1954, December 1954, and March 1971, the entirety of today's city territory came under Huaiyin Special District. In 1983, Huaiyin Special District was renamed Huaiyin City. Under its jurisdiction were 11 counties—Suqian, Shuyang, Guannan, Sihong, Siyang, Lianshui, Huaiyin, Huai'an, Hongze, Xuyi, and Jinhu—as well as 2 districts, Qinghe and Qingpu. The original county of Guanyun was transferred to Lianyungang City. In 1987, the counties of Huai'an and Suqian were reclassified as county-level cities. In August 1996, 4 counties (cities)—Suqian, Siyang, Shuyang, and Sihong—were separated from Huaiyin City and established as the prefecture-level Suqian City. At the same time, Guannan County was incorporated into Lianyungang City. In February 2001, Huaiyin City was renamed Huai'an City. The former county-level Huai'an City was re-designated as Chuzhou District within the city, and the original Huaiyin County became Huaiyin District of Huai'an City. In February 2012, Chuzhou District was renamed to Huai'an District.  In 2016, Qinghe District and Qingpu District were merged to form Qingjiangpu District, and Hongze County was renamed Hongze District.