After arriving at Hampton Roads shortly thereafter, Wilderness was assigned immediately to the 2nd Division of the North Atlantic Blockading Squadron.

On 15 July 1864, when Confederate guns located near Malvern Hill fired on Union ships, Wilderness made a night run down the James with casualties embarked, bound for the hospital at Norfolk, Virginia.

By 1 September, when Admiral Lee reported the composition of his squadron, he listed Wilderness as a "supply steam; ordered to fit out as gunboat and join (the) blockade."

On 28 October, Rear Admiral David D. Porter, the new commanding officer of the North Atlantic Blockading Squadron, issued orders to Acting Master Henry Arey, commanding the newly converted sidewheeler, to "proceed and report to the senior officer off Eastern Bar (Cape Fear River) for duty on the blockade as a chaser."

At 19:05 on the evening of 31 October, while patrolling off New Inlet, North Carolina, she spotted a strange vessel bearing south by west, heading over the bar.

Sailors from Wilderness boarded the ship, finding her cargo to consist of 540 bales of cotton, 30 tons of pressed tobacco, and 14 casks of "spirits of turpentine."

Shortly before the Union assault on Fort Fisher, the key Confederate stronghold guarding the approaches to the seaport of Wilmington, a daring plan to reduce some of the defenses by using an explosive-laden ship was put into motion.

In the final attempt, made on 23 December, Wilderness—manned by Acting Master Arey, four officers and "enough men to handle the vessel"—took Louisiana in close to the walls of Fort Fisher.

However, as Admiral Porter subsequently wrote, "I was in hopes I should have been able to present to the nation Fort Fisher and surrounding works as a Christmas offering, but I am sorry to say it has not been taken yet."

Delivering her tows soon thereafter, the side-wheel steamer supported the landings against the Confederate stronghold on 13 January 1865, taking on board a draft of troops from the transport Atlantic.

Subsequently, Wilderness took part in the occupation of former Confederate works at Smithville, North Carolina, on 19 January, Acting Master Arey and a boat crew from the ship participating directly in the operation.

Collaterally, the ship was to gain all the information she could learn about the river itself and Southern forces in the area before returning to Aiken's Landing with any dispatches which needed to be delivered.

Decommissioned on 10 June 1865, Wilderness was acquired by the Treasury Department at the Boston Navy Yard on 6 September 1865 and sailed for Baltimore, Maryland, on the 17th.

Ordered back to Florida waters upon completion of those repairs on 1 February 1884, she departed New York City on 13 March and arrived at Key West nine days later.