John Armstrong was born on October 13, 1717, in Brookborough, County Fermanagh, Ireland, now a part of Northern Ireland. He was educated and trained as a civil engineer. Armstrong later immigrated to Pennsylvania as a surveyor for the Penn family, proprietors of the colony at the time. While plotting the land of what would become Carlisle, Pennsylvania, Armstrong became one of the area's earliest European settlers and was appointed surveyor of Cumberland County. At the age of 19, his surveying services were in high demand by other settlers. Armstrong married Rebecca Lyon, and they had two sons, James in 1748 and John Jr. in 1758.

During the French and Indian War, Armstrong served as a Colonel in the Pennsylvania militia. At the time, the village of Kittanning, named from the Lenape word Kit-Han-Ne ("at the great river"), was an important settlement of the Lenape people (also referred to in colonial records as "Delaware Indians"). Some warriors from Kittanning had participated in raids against colonial settlements in Pennsylvania, Virginia, and Maryland. These attacks were part of a broader conflict fueled by European encroachment on Indigenous lands and alliances between the French and Indigenous nations.

In June 1756, Fort Granville near present-day Lewistown was attacked by a force of French soldiers and Lenape warriors. Several prisoners were taken back to Kittanning, and Armstrong's brother, Lieutenant Edward Armstrong, was killed during the raid.

On September 6, 1756, Armstrong led more than 300 frontier troops in an expedition to reach Kittanning. Among them was James Potter, a militia lieutenant from Northumberland County who would later become the namesake of Potter County and a friend of Armstrong's. Thirty miles from their destination, the group camped beneath a white oak tree—later known as "Armstrong's Oak," which stood until the early 1900s. Fearing discovery, Armstrong sent ahead a small force after noticing signs of an Indigenous campfire near the village. He left the majority of their blankets, horses, and baggage with Lieutenant James Hogg and thirteen men, who remained behind to guard the supplies at a place now called "Blanket Hill."

On September 8, Armstrong launched a surprise attack at dawn. The assault resulted in the destruction of much of the village and the deaths of over 30 Lenape people, including non-combatants. The Lenape leader, Captain Jacobs, barricaded himself and his family in a fortified cabin, which Armstrong ordered set ablaze. An explosion, believed to have been caused by stored gunpowder, destroyed the cabin. According to a 1927 article by J.W. King in the Western Pennsylvania Historical Magazine, Captain Jacobs was identified by a distinctive haircut known as the "king's son" and a pouch allegedly obtained from a French officer in exchange for Lieutenant Armstrong's boots.

Although Armstrong suffered a shoulder wound and lost 17 men, with 13 wounded and 19 missing, including casualties from a counterattack at Blanket Hill, the assault was celebrated in colonial Pennsylvania. The Philadelphia city government praised Armstrong and awarded him a medal and other gifts, commemorating the attack as a military success. The Kittanning Expedition, as it came to be known, was one of the first celebrated colonial victories during the war, though it also marked the destruction of a Native community. Today, historians acknowledge the dual legacies of such expeditions: as tactical victories for colonists and as episodes of displacement and violence against Indigenous people. In the "History of Armstrong County," Robert Smith refers to appreciative notes exchanged by the city of Philadelphia and Colonel Armstrong:

"To Col. John Armstrong: Sir: The corporation of the city of Philadelphia greatly approve your conduct and public spirit in the late expedition against the town of Kittanning, and are highly pleased with the signal proofs of courage and personal bravery given by you and the officers under your command in demolishing that place. I am, therefore, ordered to return you and them the thanks of the Board for the eminent service you have thereby done your country. I am also ordered by the corporation to present you, out of their small public stock, with a piece of plate and silver medal, and each of your officers with a medal and a small sum of money, to be disposed of in a manner most agreeable to them; which the Board desire you will accept as a testimony of the regard they have for your merit. Signed by order, January 5, 1757. ATWOOD SHUTE, Mayor."

"To the Mayor, Recorder, Aldermen, and Common Council of the Corporation of the City of Philadelphia: GENTLEMEN: Your favor of the 5th instant, together with the medals and other genteel presents made to the officers of my battalion, by the corporation of the city of Philadelphia, I had the pleasure to receive by Capt. George Armstrong. The officers employed in the Kittanning expedition have been made acquainted with the distinguished honor you have done them, and desire to join with me in acknowledging it in the most public manner. The kind acceptance of our past services by the corporation gives us the highest pleasure and furnishes a fresh motive for exerting ourselves on every future occasion for the benefit of His Majesty's service in general and in defense of this province in particular. In behalf of the officers of my battalion, I have the honor to be, gentlemen, your most obedient and obliged humble servant, Carlisle, January 24, 1757. JOHN ARMSTRONG."

Armstrong went on to lead 2,700 Pennsylvania troops during the 1758 Forbes Expedition, which led to the French evacuation and destruction of Fort Duquesne (present-day Pittsburgh). During this campaign, Armstrong developed a working relationship with George Washington, then a militia officer from Virginia.

Known in his time as the "Hero of Kittanning," Armstrong later served in the Revolutionary War. He was appointed brigadier general in the Pennsylvania militia and then received the same rank in the Continental Army in 1776. That year, he traveled to Charleston, South Carolina, where his engineering skills were used in fortifying the city’s defenses. His efforts contributed to the successful defense of Charleston Harbor on June 28, 1776, when a mixed force of Continental riflemen, Pennsylvania and South Carolina militia, and Virginia frontiersmen repelled a British landing attempt..

Armstrong returned to Pennsylvania, was promoted to Major General, and led militia troops at the battles of Brandywine and Germantown in 1777. Following these campaigns, he requested and received permission to retire from active command. Still, he continued to serve the new nation in various roles, representing Pennsylvania in the Continental Congress from 1779 to 1780 and again under the Articles of Confederation from 1787 to 1788. He also served as a county judge in Cumberland County.

Armstrong's sons carried on the family tradition of public service. James Armstrong became a physician and medical officer during the Revolutionary War and later served as a U.S. Representative. John Armstrong Jr. served as a Major in the Continental Army and also as a Member of the Continental Congress.

John Armstrong died at his home in Carlisle, Pennsylvania, on March 9, 1795, and was buried in Old Carlisle Cemetery. General James Wilkinson described him as "one of the most virtuous men who had lived in any age or country."

Armstrong County was created on March 12, 1800, from parts of Allegheny, Lycoming, and Westmoreland Counties, named in honor of Armstrong’s role in the colonial conflict at Kittanning. Commemorative plaques today mark the site of "Blanket Hill" and Armstrong's former residence. In 2006, Armstrong County observed the 250th anniversary of the Kittanning Expedition with a reenactment attended by 5,000 people. While Armstrong's legacy remains recognized, contemporary reflection also acknowledges the lasting impacts of colonial violence on the Lenape people and their descendants.