Together with 158 other Armenian intellectuals, he was arrested in 1908 and after spending half a year in Tiflis' Metekha prison (just like Hovhannes Tumanyan), he was freed on bail. Staying in the Caucasus was no longer possible, and by 1911 Isahakyan had emigrated.
Isahakyan did not believe the promises made by the government of the Young Turks, regarding self-government and autonomy of Western Armenia. Assured that the danger of Panturkism (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". 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. After the war and the Armenian Genocide, Isahakyan described through his compositions the sorrow destiny and Armenians’ heroic struggle for freedom. The poet put forward the genocide accusations, the worst part of which had taken place between 1915-1922, in "The White Book". During that period, Isahakyan expressed his ideas mainly through his social and political articles, in which he discussed the topics of the Armenian cause, reunification of Armenia and the restoration of the Armenian government. The images of the massacres are persistent in his poems, such as "Snow has Covered Everything…", "To Armenia…", and "Here Comes Spring Again".
Isahakyan was awarded with the USSR State Prize in 1946. He was a member of the Soviet Committee for Protection of Peace, and was a deputy of the II-IV Supreme Soviets of the Armenian SSR. He was awarded with two orders of Lenin and medals. He became a member of the Armenian SSR Academy of Sciences in 1943.
Isahakyan's portrait appears on the Armenian 10,000 dram bill.
Between 1899-1906 he wrote "The Songs of Haiduks", a compilation of poems that became the first creation within classical Armenian poetry dedicated to the Armenian freedom struggle.
A symbolic story portraying the Armenian politics and Armenian cause of the 19th early 20th centuries must have been "Usta Karo", an unfinished novel, the work on which had accompanied the writer through all his life. "Usta Karo will be done on the day when the Armenian cause is resolved", the master himself used to say. Ishakyan could not get used the idea of a dismembered Armenia. 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.
Isahakyan returned to the Soviet Armenia in 1926 where he published a new collection of his poems and stories (e.g. "A Pipe of Patience" - 1928). Between 1930 and 1936 he lived abroad where he acted as a friend of the Soviet Union. He later had finally moved back to Armenia where he continued his enormous social work. Among his works of that time are famous "Our historians and Our Minstrels" (1939), "To my Motherland" (1940), "Armenian Literature" (1942) or "Sasna Mher" (1937).
His poems are those of love and sorrow. His best work is "Abu-Lala Mahari" (1909–1911), while his other well-known works include "Songs and Novels" and "The Mother's Heart".
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. His creative work, filled with humanism, and a great respect to the human dignity, is deeply connected with the history and culture of the Armenian people, embracing the best traditions of the Russian and the World literature. The Russian poet Alexander Blok characterized him as a "first class poet, fresh and simple, whom one, perhaps, cannot find in Europe anymore."
Isahakyan’s works have been translated in many languages and his poems have been used as lyrics for new songs.