Originally a Boer farmer from Graaff-Reinet in the Cape Colony, and a descendant of one of the earliest Dutch settlers in South Africa, he left his home and joined the Great Trek. By way of the Orange Free State, he crossed the Drakensberg into Natal, arriving in November 1838, at a time when the emigrants there were without a recognized leader. Pretorius was at once chosen commandant-general, and he speedily collected a force to avenge the deaths of Piet Retief and his party, who had been killed under orders from the Zulu king Dingane the previous February under treacherous circumstances.
On 16 December 1838, Pretorius' force of some 500 men was attacked by over 10,000 Zulus, who were beaten off with an estimated loss of 3,000 men in what became known as the Battle of Blood River. The day was remembered as Dingane's Day by Afrikaners until 1910, when it was renamed Day of the Vow and recognised as a public holiday by the first South African government. After the fall of Apartheid in 1994, the day was kept as a public holiday as an act of conciliation to Afrikaners, but was renamed Day of Reconciliation. In January 1840, Pretorius, along with a commando of 400 burghers, helped Mpande in his revolt against his half-brother Dingane. He was also the leader of the Natal Boers in their opposition to the British. In 1842, he besieged the small British garrison at Durban, but retreated to Pietermaritzburg on the arrival of reinforcements under Colonel Josias Cloete. Afterwards, he exerted his influence with the Boers in favour of coming to a peaceful solution with the British.
He remained in Natal as a British subject, and in 1847 he was chosen by the Boer farmers there to present their grievances to the governor of Cape Colony. This sprung from the continuous immigration of natives who were assigned locations to the detriment of Boer land claims. Pretorius went to Grahamstown in order to seek an audience with the governor, Sir Henry Pottinger, who refused to see Pretorius or receive any communication from him. Pretorius returned to Natal determined to abandon his farm and once more trek beyond the British dominions.
With a considerable following, he was preparing to cross the Drakensberg when Sir Harry Smith, newly appointed governor of the Cape, reached the emigrants' camp on the Tugela River in January 1848. Smith promised the farmers protection from the natives and persuaded many of the party to remain, but Pretorius departed, and, on the proclamation of British sovereignty up to the Vaal River, fixed his residence in the Magaliesberg, north of that river. He was chosen by the burghers living on both banks of the Vaal as their commandant-general. At the request of the Boers at Winburg, Pretorius crossed the Vaal in July and led the anti-British party in their "war of freedom", occupying Bloemfontein on 20 July. In August, he was defeated at Boomplaats by Smith and retreated to the north of the Vaal, where he became leader of one of the largest of the parties into which the Transvaal Boers were divided, and commandant-general of Potchefstroom and Rustenburg, his principal rival being Commandant-General A. H. Potgieter.
In 1851, he was asked by the Boer malcontents in the Orange River Sovereignty and by the Basotho chief Moshoeshoe I to come to their aid, and he announced his intention of crossing the Vaal to "restore order" in the Sovereignty. His object, however, was rather to obtain an acknowledgment of the independence of the Transvaal Boers from the British. The British cabinet, having decided on a policy of abandonment, entertained the proposal of Pretorius, and the reward of 2000 pounds was withdrawn, which had been offered for his apprehension after the Boomplaats battle. Pretorius met the British commissioners at a farm near the Sand River, and on 17 January 1852 they concluded the convention by which the independence of the Transvaal Boers was recognized by Britain.
Pretorius recrossed the Vaal River, and on 16 March he was reconciled to Potgieter at Rustenburg. The followers of both leaders approved the convention, even though the Potgieter party was not represented. In the same year, Pretorius paid a visit to Durban with the object of opening up trade between Natal and the new republic. In 1852, he also attempted to close the road to the interior through Bechuanaland and sent a commando to the western border against Sechele.
Pretorius died at his home at Magaliesberg in July 1853. He is described by Theal as "the ablest leader and most perfect representative of the Emigrant Farmers." In 1855, a new district and a new town were formed out of the Potchefstroom and Rustenburg districts by his son, Marthinus Wessel Pretorius, and named Pretoria in honour of the late commandant-general. Marthinus Wessel Pretorius was also the first president of the Transvaal Republic.