In 1859, Skouloudis joined the famed trading house of Ralli and became a manager of its import/export business, advancing, by 1863, to head of Turkish operations.

As the "Eastern Crisis" developed into the Russo-Turkish War of 1877-78, Skouloudis was a secret emissary to the Albanian population outside Greece's borders.

He also served as a representative of the city of Ioannina in talks leading to the Congress of Berlin which readjusted the border between Greece and the Ottoman Empire after that war.

After Bulgaria's unilateral unification with Eastern Rumelia from the Ottoman Empire, Skouloudis represented the Greek government at peace talks in Constantinople in 1886.

Because of his extensive diplomatic service, the liberal Skouloudis was appointed Minister for Foreign Affairs in the conservative government of Dimitrios Rallis in 1897.

In this position, he found himself overseeing Greece's diplomatic response to its first military defeat in the Greco-Turkish War of 1897, which despite the fairly complete defeat of Greece's army, resulted in a relatively small loss of Greek territory, partly because of Skouloudis' diplomatic efforts.

In October 1915 Venizelos left Athens and would later set up a rival government in Thessaloniki and Prime Minister Zaimis resigned.

Eventually, with the abdication of Constantine in summer 1917 and the return of Venizelos triumphant to Athens, Skouloudis found himself investigated for collaboration with the former king, such as the reasons for the surrender of Fort Roupel in 1916 to Central Powers.