The cities of Arkhangelsk and Vologda, as well as many smaller towns, many of those of significant historical importance such as Veliky Ustyug, Totma, Solvychegodsk, and Kholmogory, are located in the river basin of the Northern Dvina.

Looking more closely, the Sukhona flows east and meets the north-flowing Yug River at Veliky Ustyug.

The upper Sukhona is now connected by the Northern Dvina Canal to the Volga–Baltic Waterway, which links Petersburg to Moscow.

The Sukhona flows east, eventually north-east, joins the north-flowing Yug at Veliky Ustyug and acquires the name 'Northern Dvina'.

North of Veliky Ustyg, the highway runs on the left bank of the Northern Dvina.

Shortly downstream from the confluence, the Northern Dvina is crossed by the railway connecting Konosha with Kotlas and Vorkuta.

The Northern Dvina turns northwest and receives a number of smaller rivers such as the Uftyuga and the Nizhnyaya Toyma, both from the northeast.

Near the mouth of the Pinega, the river splits into several channels, among which is the ancient selo of Kholmogory 75 kilometres (47 mi) southeast of Arkhangelsk.

On the southwest side of the delta is the naval base of Severodvinsk, the second-largest city in the region.

All administrative centers of these districts are located at the banks of the Northern Dvina, as they developed when the river was the major transportation route of the region.

The river quickly lost its role as the leading trading route, which was accelerated by the construction of the railway between Vologda and Arkhangelsk between 1894 and 1897.

The Northern Dvina was scene of several battles during the Russian Civil War, many involving the Entente interventionist army as part of their North Russia Campaign.