Wabash departed Philadelphia, Pennsylvania on September 7, 1856, stopping at Portsmouth, New Hampshire, to embark President Franklin Pierce for passage to Annapolis, Maryland.

The squadron was instrumental in foiling the expedition against Nicaragua underway by American filibuster, William Walker, who had dreamed of uniting the nations of Central America into a vast military empire led by himself.

Stateside controversy over the questionable legality of seizing American nationals in foreign, neutral lands prompted President James Buchanan to relieve Commodore Paulding of his command.

Wabash was recommissioned on May 25, 1858, Captain Samuel Barron in command, and became the flagship of Commodore Elie A. F. La Vallette's Mediterranean Squadron.

The future naval hero of the Battle of Manila Bay during the Spanish–American War, George Dewey—then a midshipman—served aboard the Wabash when she touched at her first port of call, Gibraltar, on August 17, 1858.

Wabash captured the brigantine Sarah Starr off Charleston, South Carolina, on August 3, 1861, and recaptured the American schooner Mary Alice, taken earlier by CSS Dixie.

On August 26, 1861, Wabash departed Hampton Roads, bound for Hatteras Inlet, North Carolina, to take part in the first combined amphibious assault of the war.

Wabash accompanied Monticello, Pawnee, revenue cutter Harriet Lane, the tug Fanny, and two transports, carrying over 900 troops under Major General Benjamin Butler.

Wabash was later designated the flagship of Flag Officer Samuel Francis du Pont, the new commander of the South Atlantic Blockading Squadron, and was sent to the New York Navy Yard for repairs on September 21, 1861.

After refit, Wabash departed Fort Monroe on 29 October 1861 to spearhead the Federal assault on Port Royal, South Carolina.

On August 5, 1863, CSS Juno, a small steamer on picket duty below Fort Sumter, fired upon and ran down a launch from Wabash, capturing 10 sailors and drowning two.

Wabash departed the Boston Navy Yard on November 17, 1871 and served as the flagship of Rear Admiral James Alden, commanding the Mediterranean Squadron.

She arrived at Cadiz, Spain, on December 14, 1871 and cruised throughout the Mediterranean until November 30, 1873 when she departed Gibraltar, bound for Key West, Florida.