He was born on 21 July 1414 from a modest Savonese family in Pecorile (today Celle Ligure) near Savona (Imperiale), son of Leonardo della Rovere and Luchina Monleone, under the lordship of Sigismund of Luxembourg. He entered the Franciscan order and studied philosophy and theology at the University of Pavia.
Thanks to his remarkable intellectual skills, Francesco della Rovere was able to devote himself to teaching, teaching in many Italian universities, including Venice (reader of philosophy, 1439-1441), Padua (teacher of logic, April 1444-May 1446). He was appointed Prime Minister of the Franciscan Province of Ligura (1460), and then Minister General of the Franciscans in Perugia on May 19, 1464, a post that he will manage with dedication and firmness of mind and which he will keep until 1469, eliminating the unworthy and trying to restore morality in the various monasteries. This tireless activity was rewarded, thanks to the praise of Cardinal Bessarione, with the appointment as cardinal of S. Pietro in Vincoli by Pope Paul II, on September 18, 1467. Later, he was Abbot of Sant'Eustachio di Nervesa in Treviso.
Francesco della Rovere also proved to be a refined writer and a sharp theologian. At the beginning of the 60s he composed, in opposition to the Dominicans, the treaty De Sanguine Christi, in which he defended the idea of Giacomo della Marca according to which the blood of Christ poured before the Passion would have no salvific value. The work of the theologian Della Rovere, however, tries at the same time to reconcile the idea of Della Marca with that of the Dominicans, who claimed that the blood of the Redeemer could have salvific value.
After the death of Paul II, which occurred on July 26th, 18 cardinals met in conclave on August 2nd. The election of Cardinal Della Rovere, supported by the Duke of Milan, Galeazzo Maria Sforza, was almost in the name of simony: Della Rovere's nephew, the assistant of the Conclave Pietro Riario, traded with the various cardinals for the votes to converge on his uncle . Thus, thanks to the pressures of the cardinals Latino Orsini, Rodrigo Borgia and Francesco Gonzaga, the cardinals on August 9 unanimously proclaimed Della Rovere as the new pontiff, who assumed the name of Sixtus IV in homage to the saint of the day. He was crowned on 25 August 1471 by the Cardinal-Protagonian Rodrigo Borgia, after having been consecrated first bishop by Cardinal Guillaume d'Estouteville, as we learn from recent studies of episcopal genealogy.
Sixtus IV, just elected to the papal throne, supported a crusade against the Ottoman Empire, which became extremely aggressive and threatening towards Europe. Therefore, after sending various legacies to the European states, the pontiff entrusted to cardinal Oliviero Carafa the guide of 10 papal galleys (together with the Venetian and Neapolitan galleys) to attack the Sultan Muhammad II. The quarrels between the coalitions ended in defeat when the Christian militias failed to conquer the city of Smyrna (the collection of funds from the inhabitants to support the enterprise was more successful than attempts to take the city by force). Despite this, Sixtus decided to honor Carafa's vain military exploits with a festive carnival in 1473.
The second crusade was instead dictated by the need to defend Italy from the threat of the Turks, who had conquered Otranto on 11 August 1480, a city under siege since July 28 by a fleet of 150 ships carrying eighteen thousand men. The Italian states, hitherto engaged in wars among themselves, quickly gathered in a military league. The city of Otranto was liberated on September 8, 1481. Pacifico from Novara was sent to banish the crusade.
Sixtus IV confirmed the Jubilee announced by his predecessor Paul II with the bull Salvator Noster of March 26, 1472. The Jubilee was marred by adverse events: the flooding of the Tiber and the consequent plague caused a considerable outflow of pilgrims; the Pope himself had to save himself outside Rome.
With the bull Cum Proeexcelsa of 27 February 1477, Sixtus IV established the feast (8 December) of the Immaculate Conception of the Virgin Mary, also promoting the recitation of the Rosary . He also consecrated the Sistine Chapel to the Assumption of Mary in heaven.
Sixtus consented to the Spanish Inquisition, following the issuance of a bull of November 1, 1478 establishing an inquisitor in Seville, under the political pressure of Ferdinand II of Aragon. Nevertheless, Sixtus discussed on protocol and prerogatives of the jurisdiction, was dissatisfied with the excesses of the Inquisition and took measures to condemn the most blatant abuses in 1482 but, thanks to agreements with Ferdinand and Isabella of Castile who could appoint inquisitors of their trust, was appointed the fanatic cardinal Torquemada as general inquisitor, later confirmed by Sixtus himself.
In 1478 Sixtus IV abrogated the last decrees of the Council of Constance that could limit papal authority. But in front of the Pope's social policy, the Dominican Andrea Zamometic (1420 - 1484), once a friend of Sixtus and now ambassador of Emperor Frederick III, came into conflict with the Roman court scandals (some suppose that he quarreled with Pope Sixtus for failure to appoint cardinal). When he fled Rome, he fled to Basel where he tried, on March 25, 1482, to convoke an ecumenical Council to judge the Pope but the latter, reaffirming the appeal of the clergy to the convocation of an Ecumenical Council without the consent of the Pontiff and launching the interdict on Basel (1483), managed to get the better of it. Arrested, Zamometic hanged himself in his cell in 1484.
Sixtus IV continued the sterile debate with Louis XI of France, who continued to defend the Pragmatic Sanction of Bourges (1438), which provided the royal consent to the papal decrees before they were promulgated in France and formed the unmovable keystone of the independence of the Gallican Church.
To understand the political moves of Pope Della Rovere, we must first underline the enormous influence that his relatives had on him. His pontificate, in fact, was characterized by a nepotist policy even more tenacious than that of his predecessors. Sixtus IV counted numerous relatives: 4 sisters, 2 brothers and 15 grandchildren, two of whom (Giuliano della Rovere and the scapular Pietro Riario who, prematurely died at 28, was replaced by Raffaele Riario) were elevated to the cardinal rank already from the first consistory ; instead, their nephew and former cloth merchant Girolamo Riario (for whom Sixtus IV wanted the dominion of Imola and Forlì) and Giovanni della Rovere, who was named prefect of Rome, gave his political career. Girolamo Riario influenced the foreign policy of Sisto in a preponderant way. He completely ignorant of politics and intent on personal gain, threw Sixtus IV into a series of unsuccessful wars that squandered the papal finances (which could be partially reintegrated thanks to the proceeds of the Jubilee of 1475 and the institution of the Apostolic Dataria).
The ruthless politics of the Riario and the violent character of him aroused various revolts in Rome and in the Roman Campagna in 1482. In an attempt to forge ties with the Orsini, the Riario was clearly against the Colonna and Savelli who, by reprisal, unleashed their armed bands for Rome and throughout the surrounding countryside, thus undermining the papal authority.
The first objective of the Riario was the Florence of Lorenzo the Magnificent. The Medici, displeased with Pope Sixtus for the occupation of Imola and Faenza, was in a very tense relationship even for the failure to appoint cardinal for his brother Giuliano. The Riario, intent on creating a vast principality in Tuscany, made contact with the Pazzi, bankers adversaries of the Medici for the control of the city institutions to which Sixtus IV entrusted his confidence in loans and, perhaps, even with Federico da Montefeltro. Prepared the plot, this was perpetrated on April 26, 1478 during the Mass in the Cathedral of Santa Maria del Fiore: Giuliano was killed, while Lorenzo escaped death. Lorenzo's vengeance was exemplary: the conspirators were all executed, including the archbishop of Pisa Francesco Salviati, who was hanged on the walls of the Florentine Palazzo della Signoria. Sisto, since killing a clergyman was equivalent to being excommunicated by the Church, he replied with excommunication against Lorenzo (the bull Ineffabilis et summi patris providentia of 1 June  / August 1478) and two years of war against Florence. The war against Florence was a failure, because none of the other "crypto-conspirators" intervened to save the Pope. From this useless and wasteful war, Sisto was paradoxically saved from the conquest of Otranto by the Turks in 1480: therefore came peace with Florence on December 3rd of the same year.
The peace of Lodi was once again challenged by the irresponsible attitude of Pope Sixtus. In fact, the Pope (and therefore Girolamo Riario, disappointed by the failed conquest of Tuscany), committed himself to the attack of the Duchy of Ferrara to put the same Riario on the ducal seat. The two urged the Serenissima to attack in 1482, determining the beginning of the War of Ferrara (1482-1484). Their combined assault, which saw the Venetian-pontifical victory in the battle of Campo Morto (1482), was blocked by an alliance between the Sforza of Milan, the Medici of Florence, and the king of Naples, his hereditary ally and usually strong arm of the papacy. For refusing to desist from the hostilities that he himself had instigated (and to be a dangerous rival to the papal ambitions in the Marches), Sixtus placed Venice under interdiction until 1483. Because of these constant changes in politics, Sixtus lost credit to his allies who, by isolating him, forced the pontiff to the peace of Bagnolo in 1484.
Sixtus IV died on 12 August 1484, due to a persistent fever. He is buried in the Basilica of San Pietro, in the Vatican Grottoes, where he rested in a magnificent bronze funerary monument, similar to a casket of goldsmith art by Antonio Pollaiolo. At the beginning of the twentieth century, his remains, together with those of his nephew Julius II, were transported near the altar of Santa Petronilla, on the ground and with very simple Latin inscription, still in the Vatican Basilica.