The 105th Pennsylvania Infantry was founded by Amor McKnight, a lawyer and resident of Brookville, Pennsylvania, who became one of the state's earliest responders to President Abraham Lincoln's call for volunteers to defend Washington, D.C. following the fall of Fort Sumter to Confederate States Army troops in mid-April 1861.

[7][5] Ordered to support the defenses of Washington, the regiment was transported south that fall and initially pitched its tents at Camp Kalorama on the Kalorama Heights in Georgetown, District of Columbia before it was reassigned to the 1st Brigade, 1st Division, III Corps and moved to Camp Jameson, which was located roughly a mile south of Alexandria, Virginia on the farm of Revolutionary War patriot George Mason.

[4][5] Leaving camp on March 17, 1862, the regiment took part in the siege of Yorktown and the battles of Williamsburg and Fair Oaks.

Three companies were on special duty at the opening of the action and, being unable to reach the regiment in its exposed position, fought with the 57th Pennsylvania Infantry.

At the Battle of Gettysburg, the regiment lost many men, and, after the return to Virginia, engagements followed at Auburn, Kelly's Ford, and Locust Grove in the Mine Run campaign late in November.

[11][12] The regiment then moved to Petersburg with the army, where it took part in the operations of the X Corps in August and the movements upon the Wilmington and Weldon Railroad in October and December.

[13][5] On February 20, 1865, the 105th absorbed Company C of the 2nd United States Volunteer Sharpshooter Regiment, which was disbanded on that date, and in March 1865, about 300 recruits were received.