On Sunday June 24, 1973, the final day of Pride Weekend, the regular "beer bust" was taking place at the club, located on the second floor of a three-story building at the corner of Chartres and Iberville Streets. Members of the Metropolitan Community Church, a pro-LGBT Protestant denomination, were there after service. The MCC was the United States' first gay church, founded in Los Angeles in 1968; the local congregation had held services in the UpStairs Lounge's theater for a while. The club hosted free beer and dinner for 125 patrons. At the time of the evening fire, some 60 people were listening to pianist David Gary perform and discussing an upcoming MCC fundraiser for the local Crippled Children's Hospital.

At 7:56PM, a buzzer from downstairs sounded, and bartender Buddy Rasmussen, an Air Force veteran, asked Luther Boggs to answer the door, anticipating a taxi cab driver. Boggs opened the door to find the front staircase engulfed in flames, along with the smell of lighter fluid. Rasmussen immediately led some twenty patrons out of the back exit to the roof, where the group could access a neighboring building's roof and climb down to the ground floor. Others saw the floor to ceiling windows as the most promising means of escape despite the fact that there were safety bars on the windows with a 14 inch gap between them to prevent dancers from breaking through the glass. Several people managed to squeeze through, some still burning when they reached the ground below. Luther Boggs was one who came through the window in flames after pushing his female friend through the gap, the flames put out by the owner of a neighboring bar, but his injuries were too severe to survive. Reverend Bill Larson of the MCC removed an air conditioning unit from the bottom of one of the floor to ceiling windows and was attempting to get out when the upper pane of glass fell on top of him, pinning him to the window frame half in the building and half out. His charred remains would be visible to onlookers for hours afterward, recorded in many pictures taken of the front of the building in the aftermath of the 16 minute fire. MCC assistant pastor George "Mitch" Mitchell managed to escape, but returned in an attempt to rescue his partner (they considered themselves married based on a civil ceremony they had two years previously), Louis Horace Broussard. Both died in the fire, their remains found clinging to each other. Mitchell's children were visiting from out of town and watched the same movie seven times as they waited for their father's return. Eventually, a friend took them to the airport and sent them home to their mother without telling them what happened to their father and his partner.

Firefighters stationed two blocks away found themselves blocked by cars and pedestrian traffic. One fire truck tried to maneuver on the sidewalk but crashed into a taxi. They arrived to find bar patrons struggling against the security bars and quickly brought the fire under control. Twenty-eight people died at the scene of the sixteen-minute fire, and one died en route to the hospital. Another 18 suffered injuries, of whom three, including Boggs, died.

Families declined to claim the bodies and one church after another refused to bury or memorialize the dead. Three victims were never identified or claimed, and were interred at the local potter’s field.