Comboni was born in Brescia, Italy, in a poor farming family. He was the only one of 8 children who survived childhood. He went to Verona to study in the Mazza Institute, founded by Fr. Nicola Mazza. He was ordained a priest in 1854, and three years later departed for Africa with five other missionaries from the Mazza Institute.
After a four month journey, they reached their destination of Khartoum, Sudan. Most of his fellow missionaries died, which inspired him more than ever to dedicate his life to the people of Africa. He returned to Italy in 1864 to develop a new missionary strategy, and to enlist financial and spiritual support throughout Europe.
Between several return trips to Africa, Comboni founded a mission for priests in 1867, and a mission for sisters in 1872. They became known as the "Comboni Missionaries" and the "Comboni Missionary Sisters", or, "Verona Fathers" and "Verona Sisters", respectively. He took part in the First Vatican Council as the theologian of the Bishop of Verona, and convinced 70 Bishops to sign a petition for the evangelisation of Central Africa.
In 1877, Comboni was named Bishop of Central Africa, amidst a severe two-year drought there resulting in many deaths from starvation. One year after his eighth and last trip to Africa in 1880, he died in Khartoum.