Potgieter was born in the Tarkastad district of the Cape Colony, the second child of Petronella Margaretha and Hermanus Potgieter. He grew up to be a wealthy sheep farmer and fought in the Fourth and Fifth Frontier Wars. However, like many other Boers -- farmers of Dutch, French, and German descent living in the Cape Colony -- he decided to leave the colony in 1834. Delayed by the Sixth Frontier War, Potgieter and a group of Voortrekkers under his leadership left in 1835. Other treks under Louis Trichardt and Johannes Hendrik Janse van Rensburg had preceded him. The Voortrekkers' spiritual leader, Sarel Arnoldus Cilliers, later joined Potgieter's trek.
Potgieter and his party moved inland to the present Free State, where they signed a treaty with the leader of the Baralong, Moroka. The treaty stipulated that Potgieter would protect the Baralong against the Matabele raiders, in exchange for land. The tract of land was from the Vet River to the Vaal River.
The Matabele leader, Mzilikazi, was threatened by the white incursion into what he saw as his sphere of influence, which led to the Matabele's attack on the Potgieter laager in October, 1836, at Vegkop, near the present-day town of Heilbron. The attack was beaten off, but the Matabele made off with most of the trekker oxen, crucial draught animals for the wagons. The combined trek groups of Piet Retief and Gerrit Maritz came to Potgieter's rescue. Moroka also helped with oxen. His group joined up with Retief and Maritz at Thaba Nchu, where they formed a Voortrekker government and decided to move to Natal. Potgieter was not in favour of this plan and stayed behind in the Free State
In 1838, after Piet Retief and his party were killed by Dingane, and other Voortrekker parties were attacked at the Bloukrans- and Bushmen's Rivers, Potgieter and another leader, Pieter Lafras Uys assembled a military force. To prevent schism and discord, the new Voortrekker leader in Natal, Maritz, diplomatically pronounced that both Uys and Potgieter were to be in command. However, a struggle between the hot-headed Uys and Potgieter ensued. The divided force was lured into an ambush by the Zulus at Italeni, and both Uys and his son Dirkie, were killed. The surrounded and outnumbered force fled. Potgieter was criticized for his actions, and the force was called " Die Vlugkommado" or Flight Commando. He was further accused, unjustly, of causing the death of Uys by deliberately leading the force into the ambush. He left Natal for good soon afterwards and moved to the Transvaal.
Potgieter subsequently went on to found Potchefstroom (named after him) and served as its first head of state of the Potchefstroom Republic between 1840 and 1845. Later, in 1845, he also founded Ohrigstad (originally named Andries-Ohrigstad after Potgieter himself and George Ohrig) as a trading station. Owing to a malaria outbreak, the town had to be abandoned. The inhabitants, including Potgieter, moved to the Soutpansberg area, where he founded the town Soutpansbergdorp, later renamed Schoemasdal.
After the 1842 annexation of Natal by Britain, many Natal Trekkers moved to the Free State and the Transvaal. These newcomers and their leader, Andries Pretorius, refused to accept the authority of Potgieter, and a power struggle developed. War was averted, and in 1848 a peace treaty was signed in Rustenburg. Potgieter died on the 16th of December, 1852, in Schoemasdal. A number of African chiefs who held him in very high regard came to pay their respects before his death.