On 30 November, Slidell was disembarked at Vera Cruz; however, after making his way to Mexico City, he was refused recognition by the Herrera government.

In February, she carried dispatches between Conner and Taylor as attempts were made to pressure the Mexican government into reopening negotiations; but, in March, she arrived at the Antón Lizardo anchorage, whence she could institute a blockade of Tampico if the situation deteriorated into war.

In June, scurvy struck; but attempts were made to destroy Mexican gunboats and impede the reinforcement of the town's defenses.

Through the summer, she maintained her part in the blockade; but, by September, the climate, disease, limited water and food, and relative inaction had taken its toll.

In late December, she was ordered to Brazos Santiago, whence, in January 1847, she proceeded to Lobos to cover the movement of General Winfield Scott's troops.

On the 8th, she moved toward Vera Cruz; and, on the 9th, her boats carried assault troops to Collado Beach, where Scott's force was landed, without resistance, in under five hours.

On 10 April, she had been ordered back to the United States by the Secretary of the Navy; and, in early May, she sailed for Norfolk, Virginia, carrying captured Mexican guns as cargo.

From New Granada (Panama), Davis took St. Mary's to the Jarvis and New Nantucket Islands, then returned to Central America to stand by, off Nicaragua, as William Walker fought to keep his empire there.

On 6 February 1857, St. Mary's anchored at San Juan del Sur, where she remained into the spring as Davis sought to negotiate an end to the fighting.

In late August, she set sail again and headed south to cruise off Central America; and, in February 1859, her officers and crew were relieved at Panama City.

Through that war, St. Mary's remained with the Pacific Squadron, protecting Union merchant shipping and searching for Confederate raiders.