There is much opposition to Virginia's secession vote from the western counties of the state, which are economically tied closer to western Pennsylvania and Ohio than to eastern Virginia.

Following the secession vote in Richmond in April, John Carlile, a Unionist leader from northwest Virginia, leads a meeting at Clarksburg that calls for a convention to meet at Wheeling the next month for determining what steps "the people of Northwest Virginia should take in the present emergency."

The 1st West Virginia Volunteer Infantry Regiment is also raised the same month as Union infantry, participating in the first battle of the campaign at Philippi.

To organize Union forces in the area, George B. McClellan is appointed commander of the Department of the Ohio, covering Ohio, Indiana, Illinois, western Pennsylvania, and western Virginia.

He gathers several regiments raised in Ohio, Indiana, and western Virginia and moves into Virginia in early May, moving along the Baltimore and Ohio Railroad and the Kanawha River.

West Virginia, both before and after it is granted statehood, will raise several infantry, cavalry and artillery regiments throughout the war to fight on the side of the Union.

The Confederates appoint several commanders to organize troops in western Virginia: Colonel George A. Porterfield in northwestern Virginia, and Brigadier Generals John B. Floyd and Henry A. Wise in the Kanawha Valley.

This divided command structure prevents the Confederates from coordinating their response to the Union invasion; in addition, General Robert E. Lee, commander of the Virginia militia forces, will underestimates the strength of Unionist support in western Virginia.
 

John B. Floyd's Confederate brigade attacks a Union regiment under Colonel Erastus Tyler at Kessler's Cross Lanes and routs it on August 26, temporarily securing the eastern Kanawha Valley for the Confederates.

Brigadier General William S. Rosecrans takes three brigades from Clarksburg and attacks Floyd's brigade at Carnifex Ferry on September 10.

Although the Confederates are able to hold off the Union attacks, they are outnumbered and are forced to retreat that night.

Fort Donelson, on the Cumberland River, is more defensible than Henry, and Navy assaults on the fort are ineffective.

Grant's army marches cross-country in pursuit of Tilghman's men and attempts immediate assaults on the fort from the rear, but they are unsuccessful.

On February 15, the Confederate forces under Brigadier General John B. Floyd attempt  to escape and launch a surprise assault against the Union right flank (commanded by Brigadier General John A. McClernand), driving McClernand's division back but not creating the opening they need to slip away.

Grant recovers from this temporary reversal and assaults the weakened Confederate right.

Trapped in the fort and the town of Dover, Tennessee, Confederate Brigadier General Simon B. Buckner surrenders his command of eleven thousand five men and many needed guns and supplies to Grant's demand for "unconditional surrender".

The combined victories at Henry and Donelson are the first significant Union victories in the war, and two major rivers become available for invasions into Tennessee.