Orsenigo studied at the seminary in Milan. He was ordained a priest in 1896. Since 1897 he was chaplain in Milan, later he became pastor of San Fedele in Milan. In 1912, he was finally a member of the cathedral chapter of Milan. Even as a priest in Milan, he met Achille Ratti know that soon after Pope Pius XI. should be.
Orsenigo guess Achille Ratti very, as this esteemed him. In this context, it is not very surprising that Achille Ratti after the election to the papacy Orsenigo on June 23, 1922 rose Titular Archbishop of Ptolemais in Libya and appointed Apostolic Nuncio to the Netherlands. He received his episcopal consecration on 29 June 1922, the then- Camerlengo and Cardinal Secretary of State Pietro Gasparri.
Orsenigo remained until his appointment as Apostolic Nuncio in Hungary in the summer of 1925 in The Hague. On April 25, 1930, he was Apostolic Nuncio in Germany, as had been appointed his predecessor, Eugenio Pacelli, the nuncio cardinal and recalled to Rome. His confirmation letter from the government received Orsenigo on May 2 of Reich President Paul von Hindenburg.
On May 4, 1939 Orsenigo Adolf Hitler visited on the Obersalzberg and gave him the suggestion of Pope Pius XII. prior to convene a conference of the States of Germany, France, Great Britain, Italy and Poland to counter the threat of war. However, Adolf Hitler showed only very superficial interest and referred to in his opinion existing law of the strong Germany.
On June 21, 1942 Orsenigo consecrated as consecrator the new Archbishop of Cologne, Joseph Frings, the Cologne Cathedral.
With the deepening air war Orsenigos the residence was transferred in August 1943 after Prötzel east of Berlin and was thus spatially separated from the Nunciature.
In November 1943, Orsenigo was again commissioned by Pope Pius XII. to his meeting with Adolf Hitler on the Obersalzberg, to advocate for the persecuted Jews by the Nazi regime. Also, this interview with Adolf Hitler was unsuccessful. Throughout much of the conversation Hitler Orsenigo ignored simply by going to the window and looked out.
As one of the few international diplomats in Berlin he experienced from beginning to end the rise and fall of the Nazi regime in Germany. On 8 February 1945 he resigned as nuncio in Germany down against the will of the Pope and left Berlin in the face of the advancing Soviets in the direction of Eichstätt, where he died at the age of 72 years.