Her first cruise took the frigate to Montevideo and Buenos Aires in October 1858 with the Paraguay expedition, a task force commanded by Flag Officer William B. Shubrick, after that country's firing on USS Water Witch.

She conveyed Commissioner Bowlin and served as flagship during the voyage to South America, but was not officially considered part of the expedition fleet, as she was not designed to act against Paraguay, not being able to ascend the river.

During the Civil War, Sabine was actively employed along the east coast searching for Confederate raiders.

Adams; the rescue of 500 marines and the crew of chartered troop transport Governor during a violent storm off South Carolina on 2 and 3 November 1861; the search for Vermont in March 1862, after the ship-of-the-line had been badly damaged by a storm while sailing to Port Royal, South Carolina; and the hunt for CSS Alabama in October 1862 and CSS Tacony in June 1863.

In 1867, an apprentice on Sabine, Frank Du Moulin, was awarded the Medal of Honor for rescuing a crewmate who had fallen from the rigging into the water.