He was born at Limone sul Garda, Brescia, Italy, into a family of cultivators employed by one of the rich local proprietors. Luigi and Domenica, his parents, were very attached to Daniel, being the fourth of eight children, but the only one to survive to adulthood: all the others died young, six of them in their infancy. Because of this tragedy, the family formed a very close unit, rich in faith and human values, but poor in material things. This poverty is the reason that Daniel went away to school in Verona, at the Institute founded by Father Nicola Mazza. During the years spent in Verona, Daniel discovered his calling to the priesthood, and completed his studies of Philosophy and Theology. Above all he was is entranced by the mission to Central Africa, drawn by the descriptions of the missionaries who returned from there to the Fr. Mazza's Institute. On 31 December 1854, the year of the proclamation of the Immaculate Conception of Mary, Daniel was ordained a priest by Blessed John N. Tschiderer, Bishop of Trent. Three years later he left for Africa along with five other missionaries of the Mazza Institute. He also had the blessing of his mother Domenica, who finally tells him: “Go, Daniel, and may the Lord bless you”.
After a journey of four months, the missionary expedition that included Comboni reached Khartoum, capital of the Sudan. The impact of this first face-to-face encounter with Africa was tremendous, Daniel was immediately made aware of the multiple difficulties that were part of his new mission. But labours, unbearable climate, sickness, the deaths of several of his young fellow-missionaries, the poverty and dereliction of the population, only served to drive him forward, never dreaming of giving up what he has taken on with such great enthusiasm. From the mission of Holy Cross he wrote to his parents: “We will have to labour hard, to sweat, to die: but the thought that one sweats and dies for love of Jesus Christ and the salvation of the most abandoned souls in the world, is far too sweet for us to desist from this great enterprise”.
After witnessing at the death of one of his missionary companions, Daniel, far from being discouraged, felt an interior confirmation of his decision to carry on in the mission, as he wrote: “O Nigrizia o morte!”—"Either Africa, or death".
It is still Africa and its peoples that drove Comboni, when he returned to Italy, to work out a fresh missionary strategy. In 1864, while praying at the Tomb of Saint Peter in Rome, Daniel was struck by an inspiration that led to the drawing up of his "Plan for the Rebirth of Africa", a missionary project that can be summed up in an expression which is itself the indication of his boundless trust in the human and religious capacities of the African peoples: “Save Africa through Africa”.
In spite of all the problems and misunderstandings faced, Daniel strove to drive home his intuition: that European society and the Church were called to become much more concerned with the mission of Central Africa. He undertook a tireless round of missionary appeals throughout Europe, begging for spiritual and material aid for the African missions from Kings and Queens, Bishops and nobles, as well as from the poor, simple people. As a tool for missionary animation he launched a missionary magazine, the first in Italy.
His faith in the Lord and trust for Africa lead him to establish, in 1867 and 1872 respectively, two missionary Institutes of men and of women: these become known more widely as the "Comboni Missionaries" and the "Comboni Missionary Sisters", also known as the "Verona Fathers and Sisters". With unusual courage for those days, he was the first to bring missionary Sisters into the work in Central Africa.
Daniel took part in the First Vatican Council as the theologian of the Bishop of Verona, and was able to get 70 Bishops to sign a petition for the evangelisation of Central Africa: Postulatum pro Nigris Africæ Centralis.
On 2 July 1877, Comboni was named Vicar Apostolic of Central Africa, and ordained Bishop in August of 1877: this was seen as a confirmation that his ideas and his activities, which were considered by some to be foolhardy, if not crazy, were recognised as truly effective means for the proclamation of the Gospel and the liberation of the African continent.
In 1877 and 1878 he and the missionaries in Africa were tormented in body and spirit by the tragedy of a drought, followed by mass starvation that was considered without precedent. The local population was halved, and the missionary personnel and their activities reduced almost to nothing.
In 1880, with unflagging determination, Bishop Comboni traveled to Africa for the eighth and final time, to stand alongside his missionaries: intent, also, on continuing the struggle against the pernicious Slave Trade, and on consolidating the missionary activity carried out by Africans themselves. Just one year later, overwhelmed by his labours, by many deaths in quick succession among his collaborators, and by a wave of calumnies and accusations that were a bitter burden, the great missionary fell sick himself. On 10 October 1881, only 50 years old, he died in Khartoum, among his people. But he was aware that his missionary work would not end with him: “I am dying”, he says, “but my work will not die”.