Left an orphan at the early age of thirteen, he was sent to the gymnasium (secondary school) at Ilefeld, and from there went in 1722, in the poorest circumstances, to the University of Jena in order to study law. Prof. J. F. Buddeus took him into his family, and a scholarship was arranged for him. However, he soon abandoned law for theology, took his degree in 1726, and began to give free lectures on theology.
He also took an active part in a religious union of students, in the support of the free schools for poor children established by them in the suburbs of Jena, and in the training of teachers. In 1728 Count Zinzendorf visited Jena, and Spangenberg made his acquaintance. In 1730 he visited the Moravian colony at Herrnhut. A "collegium pastorale practicum" for the care of the sick and poor was in consequence founded by him at Jena, which the authorities at once broke up as a "Zinzendorfian institution." But Spangenberg's relations with the Moravians were confirmed by several visits to the colony, and the accident of an unfavourable appeal to the lot alone prevented his appointment as chief elder of the community, March 1733.
Meanwhile his free lectures in Jena met with much acceptance, and led to an offer from Gotthilf Francke of the post of assistant professor of theology and superintendent of schools connected with his orphanage at Halle. He accepted the offer, and took up his duties in September 1732. But differences between the Pietists of Halle and himself soon became apparent. He found their religious life too formal, external and worldly, and they could not sanction his comparative indifference to doctrinal correctness and his incurable tendency to separatism in church life.
Spangenberg's participation in private observances of the Lord's Supper and his intimate connexion with Count Zinzendorf brought matters to a crisis. He was offered by the Senate of the Theological Faculty of the University of Halle the alternative of doing penance before God, submitting to his superiors, and separating himself from Zinzendorf, or leaving the matter to the decision of the king, unless he preferred to "leave Halle quietly." The case came before the king, and, on April 8, 1733, Spangenberg was conducted by the military outside the gates of Halle.
At first he went to Jena, but Zinzendorf at once sought to secure him as a fellow labourer, though the count wished to obtain from him a declaration which would remove from the Pietists of Halle all blame with regard to the disruption. Spangenberg went to Herrnhut and found amongst the Moravians his life-work, having joined them at a moment when the stability of the society was threatened. He became its theologian, its apologist, its statesman and corrector, through sixty long years. The Moravians universally referred to Spangenberg as "Brother Joseph," because like Joseph in Genesis, he tookcare of his Brethren.
For the first thirty years (1733-1762) his work was mainly devoted to the superintendence and organization of the extensive missionary enterprises of the body in Germany, England, Denmark, the Netherlands, Suriname, Georgia and elsewhere. It was on an island off Savannah that Spangenberg startled John Wesley with his questions and profoundly influenced his future career. One special endeavour of Spangenberg in Pennsylvania was to bring over the scattered Schwenkfeldians to his faith. In 1741-1742 he was in England collecting for his mission and obtaining the sanction of the Archbishop of Canterbury.
During the second half of this missionary period of his life he superintended as bishop the churches of Pennsylvania, defended the Moravian colonies against the Indians at the time of the war between France and Great Britain, became the apologist of his body against the attacks of the Lutherans and the Pietists, and did much to moderate the mystical extravagances of Zinzendorf, with which his simple, practical and healthy nature was out of sympathy. The second thirty years of his work (1762-1792) were devoted to the consolidation of the German Moravian Church.
Zinzendorf's death (1760) had left room and need for his labours at home. At Herrnhut there were conflicting tendencies, doctrinal and practical extravagances, and the organization of the brethren was very defective. In 1777 Spangenberg was commissioned to draw up the Idea Fidei Fratrum, or "compendium of the Christian faith of the United Brethren" , which became the accepted declaration of the Moravian belief. As compared with Zinzendorf's own writings, this book exhibits the finer balance and greater moderation of Spangenberg's nature, while those offensive descriptions of the relation of the sinner to Christ in which the Moravians at first indulged are almost absent from it.
In his last years Spangenberg devoted special attention to the education of the young, in which the Moravians have since been so successful. He died at Berthelsdorf on 18 September 1792. In addition to the Idea fidei fratrum, Spangenberg wrote, besides other apologetic books, a Declaration über die seither gegen uns ausgegangenen Beschuldigungen sonderlich die Person unseres Ordinarius (Zinzendorf) betreffend (Leipzig, 1751), an Apologetische Schlußschrift (1752), Leben des Grafen Zinzendorf (1772-1775), and his hymns are well known beyond the Moravian circle.