In 1786, when he was 24 years old, Onís was sent on an important mission by the Spanish government, which knew that Saxony had the most highly developed mining industry in Europe and desired to acquire experienced miners to send to its American colonies.

In April 1802, he took an active part in the negotiations for and the conclusion of the Treaty of Amiens[10][11] and, in October, he was granted the customary perks of a "secretary to the King" (Secretario del rey), including a house and an expense account.

[12] Following Napoleon Bonaparte's invasion of Spain in 1808 and with the impending abdication of Ferdinand VII, the remnant of the royal government moved to Seville,[13] where Onís continued in his capacity as longest-serving senior officer of the Ministry.

Finally, the Junta Central (the anti-French Spanish Government fighting Napoleon's brother, Joseph Bonaparte, now king of Spain as José I), decided to send him to the United States.

[23] The United States did not officially recognize Onís as ambassador until December 1815, all the while asserting that political considerations obliged it to remain neutral until the conclusion of the war in Spain[24] despite assurances of support for the cause of Spanish independence by Madison.

At the start of the War of 1812 between the United States and Great Britain, the danger of invasion of East Florida, a territory that had never been in dispute, escalated and was a constant subject of concern in Onís's correspondence with Monroe.

[32] Resisting American pressure to begin negotiations in earnest, Onís tried to delay official recognition by Madrid of the US embassy through various subterfuges, such as maneuvering for the replacement of Cevallos, which occurred on 30 October 1816.

[35] He advised the Viceroy of New Spain (Mexico), Francisco Javier Venegas, and the Governor of Cuba, the Marqués de Someruelos, of the expansionist ambitions of the growing young nation.

[39][40] The treaty consisted of 16 articles,[41] half of which settled issues that had been in dispute since 1783, ceding all the lands of the Spanish Crown located east of the Mississippi, known as the Floridas, to the United States.

Settling the most serious point of contention, determining the borders to the west and northwest of the Mississippi, was delayed until the last moment,[42] as Onís aimed at all costs to keep Texas, New Mexico and California under the dominion of Spain.

Onís returned to Europe, convinced that the alternative to signing the treaty would have been the loss of all Spanish territories as far west as the boundaries of the Rio Grande[18] and parts of the interior provinces (Provincias Internas) of New Spain.

[48] In mid-1819, Onís was awarded the Gran Cruz Americana (American Grand Cross) and the honors of Consejero de Estado (Councilor of State) and was appointed minister to St. Petersburg.