In April 1754, the French began building the preceding fort, Fort Duquesne, on the site of the small British Fort Prince George at the beginning of the French and Indian War (Seven Years' War). The Braddock expedition, a 1755 attempt to take Fort Duquesne, met with defeat at the Battle of the Monongahela at present-day Braddock, Pennsylvania. The French garrison defeated an attacking British regiment in September 1758 at the Battle of Fort Duquesne. French Colonel de Lignery ordered Fort Duquesne destroyed and abandoned at the approach of General John Forbes's expedition in late November.

In 1759 construction started on Fort Pitt, which was located next to Fort Duquesne. Named after William Pitt the Elder and finished construction in 1761.

During the Pontiac's War Indian's siege of Fort Pitt began on June 22, 1763, but they found it too well-fortified to be taken by force. In negotiations during the siege, Captain Simeon Ecuyer, the commander of Fort Pitt, gave two Delaware emissaries blankets that had been exposed to smallpox. The potential of this act to cause an epidemic among the Indians was clearly understood. Commander William Trent wrote that he hoped "it will have the desired effect." Colonel Henry Bouquet, leading a relief force, would discuss similar tactics with Commander-in-Chief Jeffery Amherst. It is unknown whether people contracted smallpox from these blankets.

During the American Revolutionary War, Fort Pitt served as a headquarters for the western theater of the war. Only a redoubt, a small brick outbuilding called the Blockhouse, remains in Point State Park as the only intact remnant of Fort Pitt. Erected in 1764, it is believed to be the oldest building still standing in Pittsburgh, and likely within the Mississippi Valley. Used for many years as a private residence, the blockhouse was purchased and preserved for many years by the local chapter of the Daughters of the American Revolution.

A re-enactor participating in one of the war reenactments was murdered in the early 1970s.