The following year, he entered the Imperial Military-medical Academy in Saint Petersburg, but was expelled in 1906 for controversial political activities.

He was transferred to Tambov to live independently under police surveillance, but soon fled again, whereafter he spent 1913–14 encouraging civil unrest in the cities of Saint Petersburg, Kharkov, and Vologda.

During the Russian Civil War of 1917-1923 he chaired the revolutionary committee of Samara province and became a political commissar in the First and Fourth Red Armies.

From 1926 to 1930 he chaired the Supreme Council of the National Economy, from 1930 to 1934 he directed Gosplan, and he served as a full member of the Politburo from 1934 until his death.

Kuybyshev was one of the initiators of the first edition of the Great Soviet Encyclopedia and served as a member of its chief editorial board.