The road has been mentioned in documents since the Middle Ages, when it connected the political capital of Muscovy with the ancestral seat of the Grand Dukes of Vladimir-Suzdal.
The Vladimir Highway was renovated in the mid-18th century when it became the westernmost section of the Great Siberian Road linking Siberia to Europe.
It is in connection with the penal function that the road figures in the works of Alexander Herzen, Nikolay Nekrasov, and Fyodor Dostoevsky (e.g., Crime and Punishment).
As a result, a wealth of bitter associations accrued to it over the course of the 19th century; they are embodied in Isaak Levitan's eponymous painting (1892), representing the Vladimirka as a "lonely track going on into the empty distance enlivened only by a church and the vast lowering sky".
[1] After the Russian Revolution, the Bolsheviks were keen to get rid of the notorious name, rebranding the Moscow section of the road as Shosse Entuziastov ("Enthusiasts' Highway").