Upon his return from Leipzig in 1895 he entered the ranks of the newly established Alexandropol committee of the Armenian Revolutionary Federation.

Together with 158 other Armenian intellectuals, he was arrested in 1908 and after spending half a year in Tiflis's Metekha prison (just like Hovhannes Tumanyan), he was freed on bail.

Isahakyan did not believe the promises made by the government of the Young Turks regarding self-government and autonomy of Ottoman Armenia.

Assured that the danger of Pan-Turkism (which he believed was aimed at the total extinction of Armenians) could be prevented by Turkey’s supporter, Germany, Isahakyan went to Berlin.

There, together with a number of German intellectuals, he participated in the German-Armenian movement, and edited the group’s journal Mesrob and co-founded German–Armenian Society.

The start of World War I and the horrifying massacres confirmed his gruesome predictions about the annihilating nature of the Young Turks government's policies.

Korney Chukovsky met him in Kislovodsk in 1926 and wrote in his diary:I've just had a visit from four Armenians, one of whom, Avetik Isaakyan, is a well-known poet.

And when we had an Armenian evening and his poems were read from the podium he just sat there in the audience, hunched forward, his hands over his face.

Seeing that Gyumri's famous satirist Poloz Mukuch did not have a tombstone twenty years after his death, Isahakyan ordered one, with the side of the tombstone reading "To Poloz Mukuch (Mkrtich Ghazarosi Melkonyan); and the other side: "A memento from the poet Avetik Isahakyan.

[3] Upon his release from the prison, 1897, he published first compilation of his poems "Songs and Wounds", however soon was arrested again for his activities "against Russia's Tsar" and sent to Odessa.

With a deep emotional pain and bitterness in his heart he continued to believe that a time would come when the Armenian people would return to their native shores.

During the Second World War of 1941–1945, he wrote patriotic poems like "Martial Call" (1941), "My Heart is at the Mountains' Top" (1941), "To the Undying Memory of S. G. Zakyan" (1942), "The Day of the Great Victory" (1945) and many other.