After martial law was declared and FEDRA took control of the government, Pittsburgh was designated as a military-controlled quarantine zone. Eventually, citizens became restless over a lack of rations, accusing FEDRA and the military of keeping food from them. A revolution was instigated by the Fireflies, causing many citizens to rise up and participate in fighting which lasted for around 14 months, with the rebels killing more soldiers and taking more parts of the city as time went on.

Eventually, the military forces of Pittsburgh were defeated and driven out of the zone, with the rebels massacring any soldiers and military supporters that remained. Anyone who refused to participate in the final battle was banished by the rebels. In addition to this, the rebels turned on the Firefly agitators who started the revolt in the first place, since the citizens thought that they did most of the fighting, and also wanted to remain independent from Firefly leadership.

After the uprising, the citizens established control over the city. The practice of killing outsiders came about after three teenagers were put on public trial for killing a family that wandered into the city. The leader, instead of punishing them, said that the teenagers had procured supplies and ordered the rest to follow their example. Several people quickly expressed outrage at this, but were killed for speaking out. Eventually, despite some hesitancy, hunting survivors became a common practice to Pittsburgh citizens. This is how the rebels became the Hunters.

Hunters refer to any survivors entering their city as "tourists". The hunters use this to their advantage by tricking tourists into thinking they are hurt. They then proceed to rob and kill them once they stop to help. Pittsburgh was abandoned by the military roughly 4-5 years before the events of the game, judging from the presence of skeletons. Joel and Ellie arrive in Pittsburgh by way of a pickup truck that Bill repaired for them. In order to pass through the city, Joel had to take a detour away from an old traffic jam. Right after the detour, they are immediately ambushed by hunters who ram the truck with a bus.

As a result, Joel crashes into a small grocery store and is forced to fight back. After escaping, they make their way through the buildings towards the Fort Duquesne Bridge, and come across the abandoned Hotel Grand with a strong Hunter presence. Players then have multiple options regarding how they tackle the hunters: stealthily take each enemy down one by one, run in guns blazing and start an all-out firefight, or sneak around the hostiles and not waste time or resources.

Joel and Ellie also snuck and/or fought their way through the Hunters and later their Humvee in the Financial District. Later, they run into Sam and Henry, members of a group of survivors who were fleeing Hartford and decided to take refuge in the city. After taking out the skeleton crew guarding the bridge, the group made their escape. Traveling through a sewer system that was formerly a safe settlement and now littered with Infected, the small group made it to a suburb outside of the city.

There, the Hunters again confronted the group with a military sniper rifle, and later the Humvee from before. The group successfully fends them off, but later was forced to flee from the horde of infected attracted by the sounds of the fight.