Dube was born in Natal at the Inanda mission station of the American Zulu Mission (AZM), a branch of the American Board of Commissioners for Foreign Missions. His father, the Rev. James Dube, was one of the first ordained African pastors of the AZM. Dube began his formal education in Inanda and Adams College, Amanzimtoti.
The Reverend William Cullen Wilcox was called in to talk to Dube who was misbehaving at the Adams School. His father James Dube was then the Congregational minister at Inanda.
In 1887 the Wilcox family were returning to the United States and John Dube and his mother persuaded the missionary couple to take Dube to America where he could further his education. The Cullens agreed on the condition that Dube was to maintain himself financially, however they advised him and William found him his first work on the road gang when he arrived in America.
Dube studied at Oberlin College and, although he studied printing and self-help, he did not graduate.
Dube was born of royal lineage and was, by right, a chief of the Qadi tribe. Because of his father's conversion to Christianity by early missionaries in pre-republic South Africa, he did not rule over the Qadi people. Dube's name was actually Ngcobo, who had the chieftaincy of the Qadi people of the Zulu.
For a missionary-educated person there was conflict between the newly arrived Western education and African traditional society. However, Dube navigated this social schism with a statesman-like ability, as in his later years, when he was able to win the trust of the Zulu royal family. It is conceivable that Dube would never have been part of the SANC, except that his teaching and discourse on the necessity of unity chimed in with the then-nascent political atmosphere. It is now fashionable for biased historians to mention Dube's conservatism as evidence of his eventual parting of ways with ANC. But, actually, the truth is that the ANC was never a radical movement on the call of such issues as universal suffrage until it was radicalised by the formation of the ANC Youth League in the 1940s.
Dube's speeches as president of a black political mass-movement have never been made available. The next formation of black people into a coherent socio-political movement was to come into being with Marcus Garvey's Universal Negro Improvement Association and African Communities League, founded in 1914. In his politics Dube was cautious and conservative, yet he was forthright on the rights of blacks and the paramount tenet of unity - he foresaw the necessity of the unity of black people long before Garvey came to the international scene.
Dube was also an educator, a speaker of note on the circuit engaging whites in lectures around the country. In 1901 he and his first wife, Nokutela Dube, founded the Zulu Christian Industrial School which is now the Ohlange High School at Ohlange, near Phoenix and EkuPhakameni. This was the first educational institution in South Africa to be founded by black people. He gave lecturers by invitation and he was awarded a Doctorate of Philosophy as a result. His role as an educator has been less documented, but he held and proposed views on education and culture that were to be used in inimical ways by the Apartheid government when it came into power in 1948 and legislating the Bantu Education Act. Dube had identified the need to combine Western education with local customs and traditions, all grounded in broad African communal behaviour. His theories on education are found in both Ukuziphatha and Isita.
He was among the pioneering men of letters who helped to establish Zulu literature. He was one of the first published Zulu authors, although the first published Zulu book was written by Magema Fuze, whose history of the Zulus, Abantu abamnyama lapo bavela ngakona (translated as "The Black People and From Whence They Came"), was published in 1922 having been written in the 1880s and early 1890s. Dube's first published work was an essay in English on self-improvement and public decency that was published in 1910. The work that was to earn him the honorary doctorate of philosophy was the essay Umuntu Isita Sake Uqobo Lwake ("A man is his own worst enemy") (1992)(text in pre-1936 Zulu old orthography). He went on to publish a historical novella that has proven to be popular and influential in Zulu canon titled Insila kaShaka ("Shaka's Body Servant") (1930). Dube also embarked on writing biographies of the Zulu royal family, especially that of King Dinizulu, making him the first biographer in African literature. There are numerous other works of less significant literary quality such as the essay Ukuziphatha [On Behaviour] (1910).
In addition to his literary works, Dube and his wife founded the first Zulu/English newspaper Ilanga laseNatali (The Sun of Natal) in 1903, a publication that in 2003 celebrated its centenary. Ilanga laseNatali is no longer independent since being bought by the then proto-political association Inkatha yeNkululelo yeSizwe in 1988, led by Mangosuthu Buthelezi, later to be known as a political party in post-apartheid South Africa called Inkatha Freedom Party (IFP). Dube wrote and edited numerous editorials for the paper and under various pseudonyms as well as publishing some indifferent poems. He nurtured journalists who later went on to become editors at his paper and contributed to the flourishing field of Zulu literature.
Dube and his first wife, Nokutela Dube, are credited with making the Enoch Sontonga song Nkosi Sikelel' iAfrika popular. This later became a national anthem after Ohlange Institute's choir used it. They played it at the South African Native National Congress meeting in 1912. It was sung after the closing prayer and the ANC adopted it as its official closing anthem in 1925.
Dube had experienced first-hand the influence of Booker T. Washington in his travels to the USA to expand his education in early 1890. He and his wife founded the Ohlange High School in 1901, a school dedicated to teaching Bantu women modern ways in order to be liberated and find a place in modern society. In his Ukuziphatha Dube had identified the Bantu woman as the weakness in developing Bantu society because of the society's restrictions on education for women and what he identified as woman's propensity to ephemera. Dube was particularly influenced by reading Washington's Up From Slavery, a book on self-reliance, the gospel that was taught by the American sage Ralph Waldo Emerson. Washington's book proved immensely influential in Bantu thought and across the black world. It was subsequently translated into several Bantu languages in South Africa, but Dube never chose to translate it, instead putting its teachings into practice. This was a feat that was never duplicated, except by Garvey and his movement and, on a minor scale, by the political figure Steve Biko in his hometown of King William's Town in the province of the Eastern Cape. Dube had been inspired by Washington's Tuskegee Institute; years later Marcus Garvey attempted to see Washington because of a similar inspiration, though he arrived in the US in 1916, Washington had died the previous year. Dube's school is still functioning today. Dube was a firm believer in self-reliance, both as an ethical and spiritual quest towards realisation of dignity and respect in the eyes of others. In Isita he preached self-reliance and the need for black people to initiate economic ventures in order to gain respect in the eyes of the world.
Nokutela and John Dube's organisation success was not matched in their marriage. Their failure to have children was seen to reflect badly on Nokutela and John fathered a child with one of their pupils. A committee was set up to investigate John, but they took no action and Nokutela felt humiliated. The couple separated in about 1914, and Nokutela moved to the Transvaal until she became ill with kidney disease. She returned to live with John Dube in Johannesburg, and died in 1917 at the age of 44. Her funeral was attended by Pixley ka Isaka Seme and other prominent members of what was to become the African National Congress.