Lucrezia Borgia, upon being told that Prince Djem died of malaria, states that he was killed by a mosquito, but it wouldn't be discovered that the disease is transmitted by mosquitoes until the 19th century. The name "malaria" literally means "bad air", and it was this bad air in swamps that was believed to cause the disease.
Prince Djem was in his thirties when Rodrigo Borgia became Pope, and died two years after Lucrezia's wedding while in French captivity.
Lucrezia, while being fitted for her betrothal dress suggests that a wedding gown ought to be white. However, white did not become a popular option for wedding dresses until 1840, after the marriage of Queen Victoria.
In reality, Prince Djem was put under custody of the Papacy in 1489, 3 years before the election of Alexander VI.
When Michaletto demonstrates the use of the garrote to Cesare, he uses a watermelon. The watermelon is clearly a modern breed, as historical watermelons had less flesh, most of their innards being filled with the skins and seeds.