[2][3] Isaac N. Seymour was assigned to the North Atlantic Blockading Squadron 20 November and 3 days later was stationed in Hampton Roads, Virginia.

[3] A month later Flag Officer Louis M. Goldsborough ordered Isaac N. Seymour to Hatteras Inlet for impending operations in the sounds of North Carolina.

She resumed her former duty and continued to give a good account of herself in the sounds until 24 August when she struck a bank and sank in the Neuse River some 3 miles above New Bern, North Carolina, while steaming upstream to cover a landing of troops.

Similar duty maintaining communications and lines of supply between Navy units in the sounds continued until 12 December when Isaac N. Seymour ascended the Neuse River with four other ships to support an Army expedition to destroy railroad bridges and track near Goldsboro, North Carolina, but the mission was aborted by low water which prevented their advancing more than 15 miles beyond New Bern.

Isaac N. Seymour departed Plymouth, North Carolina, 2 April to play an active role in the naval operations which, despite well-served batteries ashore, brought the beleaguered soldiers food and ammunition.

The high point of the expedition came 14 July when Rear Admiral Samuel Phillips Lee, flying his flag in Isaac N. Seymour, occupied Fort Powhatan, the last Confederate defense on the river below Chaffin's and Drewry's Bluff.