Bishop of Comminges from March 1295, he became archbishop of Bordeaux in 1299. He was elected pope through the manipulation of King Philip IV the Fair of France at Perugia in 1305. By creating a majority of French cardinals, Clement assured a line of French popes. His own pontificate was marked by woe, much of it caused by Philip.

Not allowing the church a role in secular affairs, Philip forced Clement to annul Pope Boniface VIII's bulls Clericis Laicos, forbidding clergy to pay subsidies to lay authorities, and Unam Sanctam, defining the pope's supreme authority. From 1307 Philip wanted to destroy the Knights Templars (Templar), a powerful religious military order of knighthood. After Philip accused the Templars of heresy, Clement arranged for a council to meet at Vienne, Dauphiné, in order to settle the issue. The prospect of this council prompted Clement to select Avignon, where he arrived in 1309, for his residence; he found it to be a more suitable centre for church administration than Rome, primarily for political reasons. The Council of Vienne (Vienne, Council of) convened in 1311. Clement approved the council's decision to charge heresy against the Spirituals, Franciscan extremists who observed absolute material poverty. In April 1312 Philip forced Clement, outside the council, to suppress the Templars. Furthermore, Clement was obliged to dissolve the Templars himself so as not to leave their extinction to Philip and to erase from the papal registers all apostolic letters against Philip and his agents.

Although he supported the election in 1308 of the German king Henry VII and his elevation as Holy Roman emperor in 1312, Clement was influenced by the Council of Vienne and by French pressure to favour King Robert of Naples when Henry prepared war against him. Consequently, Clement adopted an anti-imperial stand and in 1313 threatened Henry with excommunication. Upon Henry's death, Clement, claiming to rule while the throne was vacant, gave Robert the title of imperial vicar in Italy.

Clement openly favoured his relatives and appears to have had a large secret treasure. An adroit pontiff but timid and chronically ill from cancer, he left a notable contribution to canon law in the Clementinae, a collection of his decretals and those of the Council of Vienne later promulgated by his successor, Pope John XXII, in 1317. He made the school at Perugia a university and created chairs of Asiatic languages at Paris, France; Bologna, Italy; Oxford, England; and Salamanca, Spain. For yielding to France and complying with Philip, for turning against Henry, for practicing simony (selling ecclesiastical offices), and for transferring the papal see from Rome to Avignon, Clement was censured by Dante in Inferno XIX as “a shepherd without law, of uglier deed” and a “new Jason.” He was responsible for the “Babylonian Captivity” (1309–77), during which the papacy abandoned its traditional residence in Rome for Avignon.