Pope Innocent VIII had had two illegitimate children born before he entered the clergy "towards whom his nepotism had been as lavish as it was shameless."

In 1487, he married his elder son Franceschetto Cybo to Maddalena de' Medici, the daughter of Lorenzo de' Medici, who in return had obtained the cardinal's hat for his thirteen-year-old son Giovanni, later Pope Leo X.

His daughter Teodorina Cybo married Gerardo Usodimare and had a daughter.

Savonarola has chastised him for his worldly ambitions.

In Rome, Pope Innocent has had built for summer use the Belvedere of the Vatican, on an unarticulated slope above the Vatican Palace, which his successor will turn into the Cortile del Belvedere.

In season, he hunts at Castello della Magliana, which he has enlarged.

Constantly confronted with a depleted treasury, he has resorted to the objectionable expedient of creating new offices and granting them to the highest bidders.

The fall of Granada in January 1492 had been celebrated in the Vatican and Innocent had granted Ferdinand II of Aragon the epithet "Catholic Majesty."

In Black Africans in Renaissance Europe (N. H Minnich, Thomas Foster Earle, K. J. P. Lowe; Cambridge University Press, 2005) Minnich notes on page 281 that the position of Renaissance popes towards slavery, a common institution in contemporary cultures, varied.

Minnich states that those who allowed the slave trade did so in the hope of gaining converts to Christianity.

In the case of Innocent, he permits trade with Barbary merchants in which foodstuffs are given in exchange for slaves who could then be converted to Christianity.

King Ferdinand of Aragon has give Innocent one hundred Moorish slaves who the pope has shared out with favored Cardinals.

The slaves of Innocent are called "moro", meaning "dark-skinned man", in contrast to negro slaves who are called "moro nero".

Innocent in July 1492 falls into a fever.

He is said to have been given the world's first blood transfusion by his Jewish physician Giacomo di San Genesio, who had had him drink the blood of three ten-year-old boys.

The boys subsequently died.

The evidence for this story, however, is unreliable and may have been motivated by anti-Jewish sentiments.

Innocent VIII himself dies on the 25th of July.

A mysterious inscription on his tomb in Saint Peter in Rome states: “Nel tempo del suo Pontificato, la gloria della scoperta di un nuovo mondo” (transl. "During his Pontificate, the glory of the discovery of a new world.").

The fact is that he died seven days before the departure of Christopher Columbus for his supposedly first voyage over the Atlantic, raising speculations that Columbus actually traveled before the known date and rediscovered the Americas for the Europeans before the supposed date of October 12, 1492.

The Italian historian Ruggero Marino, in his book "Cristoforo Colombo e il Papa tradito" (transl. "Christopher Columbus and the betrayed Pope") became convinced of this after having studied Columbus's papers for over twenty-five years.