Samuel Bernstein, the factory's manager, was the brother of Max Blanck's wife and had worked for the Triangle company since its founding. After sorting out a payment issue at closing time on March 25th, he was frantically made aware of a fire in the factory. Minor fires had broken out during working hours before and been dealt with quickly, but now, Bernstein turned and saw “a big blaze” accompanied by smoke.

Von Drehle explains that the factory entrances were not at the corner of the building, where Washington Place and Greene Street intersected; instead, there were separate doors on each street, and only the Greene Street entrance was for workers. The long cutting tables that occupied much of the eighth floor had built-in bins underneath, allowing workers to efficiently dispose of scrap material, with "about ten inches of open space" between the top of the bin and the table. The fire marshal later concluded that someone had thrown a match or unextinguished cigarette butt into one of these scrap bins and that the extremely flammable cotton material and tissue paper "amounted to a virtual firebomb."

Workers, led by Bernstein, frantically tried to throw pails of water onto the fire, which grew even larger when wind made its way through the elevator shaft and the open doors. Employees rushed to the Greene Street door, stampeding toward the stairway and creating a pileup. Others, seeing this commotion, ran toward the opposite doors, "where they bottlenecked at the Washington Place elevators and at the door to the Washington Place stairs." Dinah Lipschitz, who worked on the eighth floor as a bookkeeper, tried to warn the tenth-floor workers by using an unreliable contraption called the telautograph, which allowed a message written on one piece of paper to be duplicated on another using a pen controlled by electrical signals. Her message of "FIRE!" to her tenth-floor counterpart did not go through, and after two minutes of waiting, she called to let them know of the fire. Mary Alter, the worker who answered the call, heard Lipschitz’s screamed warning and dropped the telephone. Lipschitz could not alert the ninth floor, as calls had to go through an operator at the tenth floor switchboard, and "she had simply vanished."

Meanwhile, on the eighth floor, Bernstein tried to use the fire hose to extinguish the fire, but no water came out. The flames grew rapidly, catching shirtwaist patterns hanging from the ceiling and igniting in each of the cutting tables' scrap bins. Bernstein scanned the room "and concluded that the eighth-floor workers had only moments remaining in which to escape." He began shouting at the workers, some of whom continued to make their way to the dressing rooms to collect their belongings before fleeing. A huge crowd had gathered at the Washington Place stairs, which prevented the doors from opening, as they were designed to open inward. Louis Brown, a machinist, pushed his way through the crowd and managed to unlock the doors using his key. As people flooded down the stairs, Bernstein made his way over to Lipschitz, who was frantically trying to reach the ninth-floor workers on the phone. He ordered her to leave and made his way upstairs.

On the street below, spectators gathered to watch smoke and fire billow from the windows of the Asch Building's upper floors, and eventually, workers began to jump. A passing police officer arrived around five minutes after the start of the blaze, but by that time, the fire had consumed most of the eighth floor. Officer Meehan met Louis Brown, who had unlocked the Washington Place door, and together they saved two women from jumping from the windows. They also found a large group of women who had used the fire escape locked in a factory on the sixth floor. Having rushed down the narrow fire escape, they found themselves in an L-shaped airshaft enclosed on all sides by buildings, with no way to reach the safety of the street from the bottom of the fire escape. These women pulled open the shutters of the sixth floor, which the fire had not reached, and found themselves locked in that factory instead. Officer Meehan guided them downstairs to safety, but due to the number of falling bodies, they were not allowed to leave the lobby.

Mary Alter, who had picked up the phone on the tenth floor, told another worker to call the fire department and went to find Blanck and Harris. Although the exact number of workers on the tenth floor at that time was unknown, Von Drehle estimates that it was probably close to seventy. When informed of the fire, Harris sprang into action and filled elevator cars with women, telling the operator to return right away. After the second car was loaded, he saw flames coming through the rear windows and shouted at everyone to make their way to the roof. Von Drehle writes that the reactions of the two owners to the fire reveals "a significant distinction" between them, as Blanck was "nearly paralyzed by fear and indecision," while Harris led a large group to the Greene Street stairs.

Bernstein arrived through the Greene Street doors, having been unable to enter the ninth floor due to the strength of the fire. He ordered people up to the roof, helping them through the flames and even carrying some of them. By this point, "flames in the enclosed airshaft had shattered the windows in the Greene Street stairwell," and survivors had to run through flames in order to reach the open air—"workers reached the roof gasping, coughing, and tearing at their coats and hats and scarves." The buildings surrounding the Asch Building were too tall to access, and New York University students attending lectures in the adjacent building used ladders to save those stranded on the roof.

The Fire Department arrived just ninety seconds after the first alarm had been raised at 4:45 p.m., and firefighters began making their way to the stairs through crowds of escaping workers. When they reached the seventh floor, they disconnected the house fire hose and connected their own, which had been attached to a hydrant's water supply on the street below. Upon reaching the eighth floor, they found “nothing else there but one mass of flame," with very little room between the fire and the door. They began blasting the fire with the hose as their captain, Howard Ruch, ordered more hoses to be connected to hydrants on the street below. After surveying the scene, he decided that the eighth-floor blaze had to be extinguished before they could attempt to rescue ninth-floor workers, or his men would risk being trapped themselves.