During the War of 1812, Pennsylvania forces again volunteered to defend the nation and the Commonwealth. Altogether, more than 14,000 Pennsylvanians actively served. During the Battle of Lake Erie, an artillery company provided volunteers to serve as cannoneers on Commodore Perry's fleet. That unit is known today as Wilkes-Barre's 109th Field Artillery Regiment. Future president James Buchanan was a private in the Pennsylvania militia during the defense of Baltimore.

During the Mexican War, Pennsylvania provided two regiments of volunteer militiamen from across the Commonwealth. Many of these companies that answered the call were already formed from existing regiments within Pennsylvania's militia structure.

During the Civil War, after President Abraham Lincoln called for 75,000 volunteers to fight for the union, five units from the Lehigh Valley and Lewistown (Logan Guards) were quickly assembled and sent for protection. Lincoln called them “The First Defenders.” These units, from the Lehigh Valley, are the predecessors of today's 213th Regional Support Group (RSG) based out of Allentown. More than 200 Pennsylvania Regiments took part in the American Civil War in 24 major campaigns.

On April 7, 1870, the term “militia” was replaced with the “National Guard of Pennsylvania."

In 1877, thousands of Pennsylvania Guardsman were called up to restore order during the Railroad Strike of 1877. The rioting was worst in Pittsburgh. Five Guardsman and 20 civilians were killed in the violence.

In 1898, the entire Pennsylvania division was mobilized and mustered into federal service at Mount Gretna for the Spanish-American War. Pennsylvania Guard units saw action in Puerto Rico and the Philippines.