Sapieha was born in 1867 in the castle of Krasiczyn, then part of the Austrian Empire. His family, originally from Lithuania, were members of the Polish nobility. He was the youngest of the seven children of Prince Adam Stanisław Sapieha-Kodenski and Princess Jadwiga Klementyna Sanguszko-Lubartowicza, daughter of Władysław Hieronim Sanguszko. His elder brother prince Władysław Leon Sapieha is the great-grand father of Queen Mathilde of the Belgians.
After graduating from gymnasium in Lwów in 1886, he enrolled in the Law Department at the University of Vienna, starting simultaneously law studies at Institut Catholique in Lille. In 1887 on the basis of his certificate from the University of Vienna Sapieha continued studies at the Jagiellonian University in Kraków. After two years he passed the examination and returned to Vienna for further studies, where he remained until 1890, obtaining the certificate of completion. In the same year he began theological studies at the University of Innsbruck, and in 1892 signed up for the third year of seminary studies in the Roman Catholic Archdiocese of Lviv.
After returning to the home country in 1897, he was designated vice-rector of the diocesan seminary in Lwów, where he worked until 1901. He resigned because he was discouraged by the imposed rules of education of young priests. After a half-year trip across the United States of America, he was designated a vicar of the St. Nicholas congregation in Lwów in October 1902. In 1905 Sapieha was appointed a papal chamberlain, and sent to Rome where he was a consultant on matters concerning the Roman Catholic Church in Poland, in the annexed territories, the realization of an idea by Lwów Armenian Catholic Archbishop Józef Teodorowicz (who was the Sapieha's long-term friend) to have a representative of the Roman Catholic Church in Poland at the Roman Curia.
He was educated at the Pontifical Gregorian University in Rome, where he was also ordained as priest on 1 October 1893 by Bishop Jan Puzyna de Kosielsko (later Bishop of Kraków and Cardinal). Father Sapieha did pastoral work in the Diocese of Lemberg, in whose seminary he served as a faculty member for four years until becoming its rector. In October 1895 he started further studies in Rome, where he obtained a doctorate of civil and canon law at the Pontifical Ecclesiastical Academy. At the same time he studied diplomacy at the Pontifical Academy of Ecclesiastical Nobles.
Sapieha was appointed Bishop of Kraków on 24 November 1911 and was consecrated by Pope St. Pius X in the Sistine Chapel on 7 December of the same year. In 1915, he established a relief committee for victims of World War I.
After World War I, Sapieha became a vocal opponent of the new concordat negotiated between the Holy See and the newly resurrected Polish state. He argued that the Polish Church should be completely independent of the state and that its primate should be the Archbishop of Warsaw. This attitude led to a conflict with Cardinal Achille Ratti, Pope Benedict XV's nuncio who himself later became Pope, during the first post-war congress of Polish bishops in Gniezno held 26–30 August 1919. Sapieha thought that the Polish should decide its affairs without outside influence and asked Ratti to leave the conference room. Sapieha was not elevated to the cardinalate by Ratti after he became Pope Pius XI in 1922.
In 1922, Sapieha was elected senator from the Christian Union of National Unity party. He ordered a memorial service and issued a proclamation on the assassination of Gabriel Narutowicz. It was the only speech he delivered as a senator because papal mandate at the time prohibited clergy from holding public office. He resigned on 9 March 1923.
Sapieha was appointed Metropolitan Archbishop in 1925 when the Diocese of Kraków was elevated to the rank of Archdiocese. He received a degree honoris causa from the Jagiellonian University in 1926. In September 1930, after opposition leaders were arrested and placed in confinement at Brest Fortress, Archbishops Sapieha and Teodorowicz strongly criticized the government. Despite this, and other occasional disagreements with the government, Sapieha was awarded the Order of the White Eagle in 1936.
In 1937, Sapieha, who had opposed the Pilsudski regime (sanacja), made the controversial decision to move Piłsudski's body, within Wawel's Cathedral, from St. Leonard's Crypt to the crypt under the Silver Bells.
In 1939 he asked Pope Pius XI to accept his resignation due to age and failing health, but the pope refused. After the death of Pius XI, he repeated his request to the new pope, Pius XII on 19 June 1939. In anticipation of the upcoming war and at Józef Beck's instigation he withdrew his resignation.
During World War II, while Primate August Hlond was in France, Sapieha was the de facto head of the Polish church in jurisdictions directly annexed by the Third Reich (primate Hlond was represented by Walenty Dymek, auxiliary bishop of Poznań) and was one of the main leaders of the nation. One of the most important organisations to which he belonged was the National Council of Welfare, created on the model of Caritas. From the war's start of the Nazi occupation, he was an independence activist, working with the Polish government-in-exile.
In August 1944, Sapieha was forced to operate the Polish seminary in secret because the Germans began killing seminarians whenever they found them. He moved his students (including the future Pope John Paul II, Karol Wojtyła) into the Bishop's Palace in Kraków to finish their training during the Nazi Occupation of Poland.
Sapieha's biographer, Jacek Czajkowski describes the circumstances of the archbishop being invited by Governor Hans Frank to Hitler's birthday party in April 1942. He told the German official: No! They are not going to change anything, but they will take a photograph of me and write that a Polish bishop arrived at Hitler's birthday party with best wishes. Tell him I will not come. Another such anecdote recalls when governor Hans Frank ordered the archbishop to hand him the keys to the Wawel Castle. Sapieha replied: But don't forget to give them back to me when you will be leaving Wawel.
In March 1945, he initiated the publication of Tygodnik Powszechny. He was created Cardinal-Priest, of the title of Santa Maria Nuova, on 18 February 1946. On 1 November 1946 he conferred priestly ordination on Karol Wojtyła in the chapel of his episcopal residence. After the Kielce pogrom he provided aid for the affected Jews.
Sapieha knew Karol Wojtyła (later John Paul II) was destined to become a priest when a young Karol delivered a welcoming speech during the archbishop's visit to his school. Some people consider him a mentor of Pope John Paul II. In 1949, he proposed that Stefan Wyszyński, Metropolitan Archbishop of Gniezno and Warsaw since 12 November 1948, should be termed Primate of Poland.
The following year (1950), he wrote letters to then-Polish president Boleslaw Bierut protesting Bierut's repression of the church. Sapieha died on 23 July 1951, and his funeral on 28 July turned into a political demonstration. He was buried in the Wawel Cathedral, in a crypt under the confessional of St. Stanislas.
In the 2005 CBS miniseries Pope John Paul II, Archbishop Sapieha was portrayed by American actor James Cromwell.