Hotshot firefighter Jack Morrison (Joaquin Phoenix) saves a man's life in a massive four-alarm fire in a 20-story concrete grain elevator/warehouse in the Canton waterfront neighborhood of Baltimore, Maryland. However the grain being stored in the warehouse explodes, causing Jack to fall through several floors and break his leg. The film follows the efforts of the other men in his unit, Ladder Company 49, led by the commands of Deputy Chief Mike Kennedy (John Travolta), Jack's mentor, to rescue him while Morrison tries to reach a safe area of the burning structure. Interspersed with the current rescue efforts are a series of flashbacks showing how Jack joined the fire department, his first meeting (at a supermarket) with the woman who would eventually become his wife (Jacinda Barrett), his relationship with his children, and the bonds he formed and the trials and tribulations he endured with his fellow firefighters.
After graduating from the fire academy, Jack is sent to work on Baltimore City Fire Department (BCFD) Engine Company 33, in the busiest firehouse in the city. Quartered with Engine 33 is Ladder Company 49. On Engine 33, Jack learns the ropes of firefighting. He quickly becomes close friends with his fellow firefighters, including Mike, his Captain at the time. Jack's first fire takes place at a burning vacant rowhouse. Engine 33 and Ladder 49 respond and are the first companies on the scene. Jack and Mike enter the building with a hose line and tackle the blaze, with Jack on the nozzle of the hose. They quickly and triumphantly extinguish it.
After some time working on Engine 33, Jack arrives at the scene of another vacant rowhouse fire, where a fellow firefighter from Ladder 49, Dennis Gauquin (Billy Burke), dies after falling through the roof of a building. After a quarrel between the firefighters, the Captain tells them to stick together. Later, numerous firefighters attend Dennis's funeral. Jack decides, although it is more dangerous, to take his late friend's position as a "truckie", a search and rescue member on Ladder 49 by transferring to the Truck.
As the years go by, Jack suffers some traumatic experiences, including rescuing a man from the ledge of a burning high-rise building in Downtown Baltimore, and witnessing another friend and fellow firefighter from Ladder 49, Tommy Drake (Morris Chestnut), suffer severe burns following a steam explosion at an industrial building. He finds the work rewarding, but his wife initially worries about his safety and opposes the change. However, she eventually accepts his new role and even talks him out of taking an administrative position that Mike, who has now become a Deputy Chief, offers him.
One Christmas Eve, Jack and the members of Engine 33 and Ladder 49 respond to a burning apartment building. Jack is able to rescue a young girl trapped in an engulfed apartment, but is briefly trapped himself before being rescued by a fellow Firefighter from Ladder 49, Leonard "Lenny" Richter (Robert Patrick). Both men receive the department's Medal of Valor for their actions.
Back at the grain building fire that opened the film, Jack's fellow firefighters become extremely determined to rescue him, and Jack does his best to reach the only possible safe area Mike tells him about. However, upon reaching that room he sees that the only exit is cut off by raging flames. Out of air and with the heat intensifying, Jack realizes that his situation is hopeless. He radios Mike to pull his men back so no one else will be killed or hurt while trying to rescue him, and accepts his fate to die in the fire. Mike reluctantly agrees and commands all rescue units to evacuate the building, devastating Mike.
At Jack's funeral, Mike delivers an emotional eulogy in celebration of Jack's life, which inspires a standing ovation from friends and family in attendance. Jack's body is then carried to his resting place, with full honors, on the back of Engine 33 in a typical fireman's funeral procession. The film ends with Mike and the guys en route to a call while the former flashes back to Jack and his fellow firefighters going to fires and a final shot of Mike and Jack coming out of Jack's first ever burning building in triumph.
John Travolta as Deputy Chief (formerly Captain) Mike Kennedy, Deputy Chief 1 (formerly Engine Company 33)
Joaquin Phoenix as Firefighter Jack Morrison, Ladder Company 49 (formerly Engine Company 33)
Jacinda Barrett as Linda Morrison
Morris Chestnut as Firefighter Tommy Drake, Ladder Company 49 Tillerman
Balthazar Getty as Firefighter Ray Gauquin, Ladder Company 49
Robert Patrick as Firefighter Leonard "Lenny" Richter, Ladder Company 49
Billy Burke as Firefighter Dennis Gauquin, Ladder Company 49
Tim Guinee as Captain Tony Corrigan, Ladder Company 49
Kevin Chapman as Frank McKinney, Engine Company 33
Jay Hernandez as Probationary Firefighter Keith Perez, Engine Company 33
Kevin Daniels as Firefighter Engineer Don Miller, Engine Company 33
Steve Maye as Firefighter Pete Lamb, Engine Company 33
Robert Logan Lewis as Firefighter Ed Reilly, Ladder Company 49
Spencer Berglund as Nicky Morrison
Brooke Hamlin as Katie Morrison
Sam Stockdale as Himself
Paul Novak, Jr. as the Voice of Ladder 49, The Dispatcher
Mayor of Baltimore Martin O'Malley as himself