Karl was born at sea[3][4] near Lisbon, Portugal into the prominent Uradel German House of Nesselrode, which originated in the Bergisches Land near the Rhine.

[6] He was present at the inconclusive Battle of Eylau in January 1807, fought by Count von Bennigsen, and assisted at the negotiations of the Peace of Tilsit[6] (July 1807), for which he was commended by Spanish Bonapartist Diego Fernandez de Velasco, 13th Duke of Frías (who in 1811 would die in exile in Paris).

Following the Congress of Erfurt in 1808, Nesselrode was secretly accredited by Alexander to serve as his unofficial channel of information between himself and Talleyrand and the marquis de Caulaincourt, formerly ambassador in St Petersburg, both of whom were hostile to Napoleon's policy of aggression.

[6] Nesselrode was present at the battle of Leipzig and accompanied the invading army to Paris; he negotiated the capitulation of Auguste de Marmont and Édouard Mortier at Clichy, and signed the Treaty of Chaumont on 1 March 1814.

His former relations with Talleyrand facilitated negotiations in Paris, and his influence with the emperor was used in favour of the restoration of the Bourbons, and, after the Battle of Waterloo, against the imposition of a ruinous war indemnity on France.

[6] Nesselrode became State Secretary in 1814 and was the head of Russia's official delegation to the Congress of Vienna, but for the most part Alexander I acted as his own foreign minister.

He was married to Russian noblewoman Maria Guryeva (1786–1849) and had issue: Foods named in his honour but devised by his chef M. Jean Mouy[11] using chestnut puree[12] are-