Soon after being commissioned, Tyler participated in the attack on the Confederate forces in Hickman and Columbus in Kentucky, doing battle with the CSS Jackson.

Between assaults on the two forts, Tyler joined USS Conestoga and Lexington moving along the Tennessee River, destroying an important railroad bridge and capturing three Confederate gunboats, most notably the CSS Eastport which was converted into an ironclad for Union service.

In the Battle of Shiloh, when Confederate forces under General Albert Sydney Johnston surprised Grant's troops in southwestern Tennessee near Pittsburg Landing and began pushing them back into the river, Tyler and Lexington brought their guns to bear when the Confederates attempted to protect their right flank by anchoring it on the river bank.

On 19 April 1862, Tyler moved farther south where she captured the Confederate transport Albert Robb and burned another Southern ship, Dunbar.

10 on the Mississippi, the North shifted the emphasis of its war in the west to conquering that mighty river in an effort to divide the Confederacy in two.

During the first phase of the siege of Vicksburg, Tyler participated in the joint Army-Navy expedition up the Yazoo River to establish a landward advance on the Confederate stronghold.

In mid-January, she joined other units of the squadron in escorting Army transports to Fort Hindman which guarded Arkansas Post on the invasion route to Little Rock.

Tyler received surprise delivery of steamboat Lady Walton, originally commandeered by the Confederacy for food transport, but which now flew under a flag of truce.

Her last major combat with the Confederates came on 24 June 1864 far up the White River near Clarendon, Arkansas, when she engaged the Southern shore batteries which damaged and captured the gunboat Queen City.

The Tyler was pressed into rescue duty with a volunteer crew to assist in the steamboat Sultana disaster, north of Memphis on 27 April 1865, as her regular complement had recently been discharged.