He was born in Fuyuanshui Village (福源水村), Hua County (traditional Chinese: 花縣; Cantonese Yale: Fa Yuen, now Huadu (花都市)), Guangdong to Hong Jingyang (洪競揚) and Wang-shi (王氏). His grandfather was Hong Guoyou (洪國游), who was, like his ancestors, a farmer. He later moved to Guānlùbù Village (官祿㘵村). His wife (Queen) was Lai Xiying (賴惜英).

Hong started studying at a school called Book Chamber House (書房閣) at age seven. He was able to recite the Four Classics after five or six years. At around the age of fifteen his parents were no longer able to afford his schooling, so he became a tutor to other children in his village and continued to study privately. He took the local preliminary examinations and came first, so at the age of 22 in 1836, he took the first-degree (秀才) civil service examinations in Guangzhou. Unsurprisingly, he failed, as imperial examinations had a pass rate of 1%. He retook the test four times, but never succeeded. This was partly due to being unable to secure a bribe to the Manchu officials. He later attained the position of instructor (塾師) at Book Chamber Building and several schools in Lianhuatang (蓮花塘) and other villages.

On his visit to Guangzhou to take the civil service examinations in 1836, Hong heard a Christian missionary preaching. While there he received translations and summaries of the Bible written by the Christian missionary Liang Fa. The following year Hong failed the examinations again and apparently suffered a nervous collapse. During his recovery in 1837 he had a number of mystical visions. One involved an old man who complained to Hong about men worshiping demons rather than him. In a second one he saw Confucius being punished for his faithlessness, after which he repented. In yet another he dreamed angels carried him to heaven where he met a man in a black dragon robe with a long golden beard who gave him a sword and a magic seal, and told him to purify China of the demons. Several years later he would interpret this to mean that God the Heavenly Father, whom he identified with Shangdi from the Chinese tradition who revealed himself to be Jesus Christ, wanted him to rid the world of demon worship. His friends and family said that after this episode he became authoritative, solemn and taller in height.

It was not until 7 years later that Hong took the time to carefully examine the religious tracts he had received. In his house Hong burned all Confucian and Buddhist statues and books, and began to preach to his community about his visions. His earliest converts were relatives of his who had also failed their examinations and belonged to the Hakka minority, Feng Yunshan and Hong Rengan. He joined with them to destroy idols in small villages to the ire of local citizens and officials. Hong and his converts' acts were considered sacrilegious and they were persecuted by Confucians who forced them to leave their positions as village tutors. Hong Xiuquan and Feng Yunshan fled the district in 1844, walking some 300 miles to the west to Guangxi, where the large Hakka population was much more willing to receive his teachings. As a symbolic gesture to purge China of Confucianism, he asked for two giant swords, three-chi (about 1 metre) long and nine-jin (about 5.5 kg), called the "demon-slaying swords" (斬妖劍), to be forged.

Hong then preached to a large number of charcoal burners on Zijing Mountain (紫金山) in Guiping District (桂平縣), who mostly belonged to the Hakka minority like Hong himself, and readily joined him. He preached a mix of communal utopianism, evangelism and his idiosyncratic quasi-Christianity. While proclaiming sexual equality, the sect segregated men from women and encouraged all its followers to pay their assets into a communal treasury. By the end of the 1840s, Hong had a sizeable following which he called the God Worshippers (拜上帝會), but local officials were still attempting to suppress his religious movement after his move to Guangxi.

Hong stayed at the Yuan Floral Hall (袁氏花厅) in Shiling (c. 1845 - 1847) where he studied, preached, developed his revolutionary theory and wrote many of his famous works.

In 1847 Hong studied with the American Southern Baptist missionary Reverend Issachar Jacox Roberts for two months in Guangzhou, during which time he gained most of his knowledge of Christianity. He formally studied the Old Testament. After Hong asked Roberts for aid in maintaining his sect, Roberts (wary of people converting to Christianity for economic aid) refused to baptise him.

Most of Hong Xiuquan's knowledge of the scriptures came from the books known as " Good Words to Admonish the Age" by a Local Chinese Preacher Liang Fa as well as a localized Bible translated into Chinese. Many western missionaries were jealous of Hong Xiuquan and his local ministry and made up things about him that were not true, including the idea that he was not baptized. "Hong and his cousin were both baptized according to the way prescribed in the pamphlet "Good words to admonish the age".

When Hong returned to Guangxi, he found that Feng had accumulated a following of around 2,000 converts. Guangxi was a dangerous area at this time with many bandit groups based in the mountains and pirates on the rivers. Perhaps due to these more pressing concerns, the authorities were largely tolerant of Hong and his followers. However, the instability of the region meant that Hong's followers were inevitably drawn into conflict with other groups, not least because of their predominately Hakka ethnicity. There are records of numerous incidents when local villages and clans, as well as groups of pirates and bandits, came into conflict with the authorities, and responded by fleeing to join Hong's movement. The rising tension between the sect and the authorities was probably the most important factor in Hong's eventual decision to rebel.

By 1850 Hong had between 10,000 and 30,000 followers. The authorities were alarmed at the growing size of the sect and ordered them to disperse. A local force was sent to attack them when they refused, but imperial troops were routed and a deputy magistrate killed. A full-scale attack was launched by the government forces in the first month of 1851. In what came to be known as the Jintian Uprising, after the town of Jintian (now Guiping) where the sect was based, Hong's followers emerged victorious and beheaded the Manchu commander of the government troops. Hong declared the foundation of the "Heavenly Kingdom of Transcendent Peace" on 11 January 1851.

Despite this evidence of forward planning, Hong and his followers faced immediate challenges. The local Green Standard Army outnumbered them ten to one, and had recruited the help of the river pirates to keep the rebellion contained to Jintian. After a month of preparation the Taipings managed to break through the blockade and fight their way to the town of Yongan (not to be confused with Yong'an), which fell to them on 25 September 1851.

Hong and his troops remained in Yongan for three months, sustained by local landowners who were hostile to the Manchu Qing Dynasty. The imperial army regrouped and launched another attack on the Taipings in Yongan. Having run out of gunpowder, Hong's followers fought their way out by sword, and made for the city of Guilin, to which they laid siege. However, the fortifications of Guilin proved too strong, and Hong and his followers eventually gave up and set out northwards, towards Hunan. Here, they encountered an elite militia created by a local member of the gentry specifically to put down peasant rebellions. The two forces fought at Soyi Ford on 10 June 1852 where the Taipings were forced into retreat, and 20% of their troops were killed. But in March 1853 Taiping forces managed to take Nanjing and turned it into the capital of their movement.

Hong Xiuquan ruled by making frequent proclamations from his Heavenly Palace, demanding strict compliance with various moral and religious rules. Most trade was suppressed and property socialized. Polygamy was forbidden and men and women were separated, although Hong and other leaders maintained groups of concubines.

Yang Xiuqing was a fellow Taiping leader (the "East King") who had directed successful military campaigns and who often claimed to speak with the voice of God. Hong became increasingly suspicious of Yang's ambitions and his network of spies; in 1856 he had Yang and his family murdered.

Following a failed attempt by the Taiping to take Shanghai in 1860, the Qing forces, aided by Western officers, slowly gained ground.

Some sources say Hong committed suicide by taking poison on 1 June 1864 at the age of 52 after Qing authorities finally gained a decisive military advantage and all hope of maintaining his kingdom was lost. However, in other sources, he was said to have died of illness. Hong Rengan, Hong Xiuquan's cousin, said his illness was caused by "eating manna" -- a command taken from the Bible that Hong had given to his people as they starved. On 30 July 1864, Qing found Hong's body. He was succeeded by his teenage son, Hong Tianguifu. The Taiping Rebellion was put down by Qing forces later in 1864.

Views and opinions on Hong differ greatly. The Chinese communists under Mao Zedong generally admired Hong and his movement as a legitimate peasant uprising that anticipated their own. Sun Yat-sen came from the same area as Hong Xiuquan and is said to have identified with Hong since his childhood days. In 1959 the PRC established a small museum, Hong Xiuquan's Former Residence Memorial Museum (洪秀全故居紀念館), in his birthplace where there is a longan tree planted by him. The museum's plate is written by the famous literary figure, Guo Moruo (郭沫若) (1892 – 1978). The residence and Book Chamber Building were renovated in 1961.

Hong Xiuquan has been compared to Falun Gong founder Li Hongzhi in that he rallies a large number of people behind a religious or spiritual cause to challenge the status quo, although Li's political intentions have been of intense debate.