The 1644 papal conclave was called upon the death of Pope Urban VIII. It lasted from 9 August to 15 September 1644; the cardinal electors chose Cardinal Giovanni Pamphili, who took office as Pope Innocent X.

Pope Urban VIII died on July 29, 1644. His reign, which included the costly First War of Castro, had been financially troubling for Rome and for the Roman Catholic Church. The conflict for control of the Church between Spain and France and the ongoing Thirty Years' War meant many cardinals arrived at the conclave seeking a compromise that would bring stability to the Church.

But Urban's reign had also subjected the Church to his notorious nepotism. He had appointed three family members as Cardinals; his brother Antonio Marcello Barberini and his two nephews, Francesco Barberini and Antonio Barberini. His nephews, especially, were keen to retain the wealth, power and property they had amassed during their uncle's reign and both sought to move the conclave in their favour.

They started by hiring, it was rumoured, bands of brigands and mercenaries to roam the streets of the city causing trouble, creating noise and generally making it uncomfortable for the cardinals inside the conclave.

Anne of Austria, French Queen Mother and sister to Philip IV of Spain, was adamant that none of the older cardinals appointed by the pro-Spanish Pope Paul V should be elected to the Papal throne.^{[citation needed]}

Francesco Barberini sided with the cardinals loyal to Spain. Urban VIII had been a strong francophile and the mood of the conclave was with Spain from the beginning. Antonio, at the direction of Cardinal Jules Mazarin, sided with the cardinals loyal to France and was supported with funding from the French with which he was to buy wavering votes. Maria Antonietta Visceglia suggests that it may have been part of Spain's strategy to split the influence of the Barberini family.

With the Habsburgs in Spain as well as the Empire, the results of a papal election often depended on the strength, or lack thereof, of anti-Spain groups, and whether these could unite. Conclave protodeacon Cardinal Carlo de' Medici led a prestigious coalition of non-aligned Italian cardinal-princes connected to the Roman aristocracy. Urban's practice of concentrating power and curial appointments in his family and those related to his relatives came as a disappointment to those very cardinal-princes instrumental in his election.

Antonio Barberini continued to promote the candidacy of Cardinal Sacchetti, in accordance with the French policy. Urban VIII and his family had been so overly partial to the French that the Imperialists and the Spanish were determined that no supporter of French interests would be elected. On August 9, Spain's Cardinal Gil de Albornoz presented a veto against Sacchetti, signed by the king. Cardinal Antonio Barberini let it be known that the Barberini were prepared to stay in conclave until everyone died before they allowed someone who was not a member of their faction to be elected pope, and that their candidate was Sacchetti. The effect, however, was to increase opposition to Sacchetti.^{[citation needed]}