[3] In Sublimis Deus, Paul III declares the indigenous peoples of the Americas to be "truly men and that they are not only capable of understanding the Catholic Faith but, according to our information, they desire exceedingly to receive it", and denounces any idea to the contrary as directly inspired by the "enemy of the human race".

He goes on to condemn their reduction to slavery in the strongest terms, declaring it null and void for any people known as well as any that could be discovered in the future, entitles their right to liberty and property, and concludes with a call for their evangelization.

With the realization that the Americas represented regions of the Earth of which the Europeans were not aware earlier, there arose intense speculation over the question whether the natives of these lands were natural slaves (and perhaps lesser humans) or not.

Gustavo Gutierrez describes Sublimis Deus as the most important papal document relating to the condition of native Indians and that it was addressed to all Christians.

[9] Toyin Faola asserts that the bull related to the native populations of the New World and did not condemn the transatlantic African slave trade stimulated by the Spanish monarchy and the Holy Roman Emperor.

[16] According to James E. Falkowski, Sublimis Deus had the effect of revoking Pope Alexander VI's bull Inter caetera but still leaving the colonizers the duty of converting the native people.