He was born in Lisbon, Portugal where his father (d. 1810), a count of the Holy Roman Empire, was the ambassador of the Russian tsar. In deference to his mother's Protestantism he was baptized in the chapel of the British Embassy, thus becoming a member of the Church of England. Nesselrode's Germanic roots were emphasized by his education in a Berlin gymnasium, his father having been appointed ambassador to the Prussian court about 1787.
At the age of 16 he entered the Russian Navy where, with his father's influence, he secured the position of naval aide-de-camp to Tsar Paul, (Russian: Па́вел I Петро́вич; Pavel Petrovich) (October 1 [O.S. September 20] 1754 – assasinated on March 23 [O.S. March 11] 1801), who was the Emperor of Russia between 1796 and 1801.
He then moved to the army, and entered diplomatic service under Paul I son and successor, Tsar Alexander I. He was attached to the Russian embassy at Berlin, and transferred thence to the Hague.
In August 1806 Nesselrode received a commission to travel in South Germany to report on the French troops; he was then attached as diplomatic secretary to Generals Kamenski, Buxhoewden and Bennigsen in succession.
He was present at the unconclussive Battle of Eylau in January 1807, fought by Count Von Bennigsen and assisted at the negotiations of the Peace of Tilsit, (July 1807), whereby Spanish Bonapartist Diego Fernandez de Velasco, (deceased in Paris in the exile in 1811), 13th Duke of Frías, congratulated and seated at table with Napoleon I .
Nesselrode became State Secretary in 1814 and was the head of Russia's official delegation to Congress of Vienna, but for the most part Alexander I acted as his own foreign minister. In 1816, Nesselrode became Russian foreign minister, sharing influence with Count John Capodistria until the latter's retirement in 1822.
For forty years, Nesselrode guided Russian policy and was a leading European conservative statesman of the Holy Alliance. Between 1845 and 1856, he served as Chancellor.
One frequently overlooked facet of his activity involved Nesselrode's attempts to penetrate Japan's self-isolation. In 1853 he dispatched Yevfimy Putyatin with a letter to the Shogun; Putyatin returned to St. Petersburg with the favorable Treaty of Shimoda.
Nesselrode's efforts to expand Russia's influence in the Balkans and Mediterranean led to conflicts with Turkey, Britain, the then Kingdom of Sardinia, the then Duchy of Savoy and France, allied in the Crimean War (1853-1856). Britain and France were concerned by Russia's growing influence and were determined to support Turkey and so restrict Russia.