The Great Fire features a diverse cast of characters, each symbolizing the unique experiences of different city sections during the disaster that affected over a hundred thousand people. Among the historical figures involved, the O'Learys have become the most recognized, largely due to the tale of their cow allegedly starting the fire. However, Murphy dismisses this theory, referencing eyewitness accounts that confirm Catherine O'Leary could not have been in the barn when the fire ignited.

The fire initially started as a minor incident, affecting less than a city block. A series of missteps and unfortunate events soon escalated it into an uncontrollable inferno. Murphy cleverly reflects the fire's expansion in his writing style. When the fire is still small, he limits perspectives to the O'Learys and their immediate neighbors. As the fire spreads, Murphy broadens his narrative to include more people. For example, when a witness attempts to activate the fire alarm at a nearby drugstore, the cast of characters expands to include unhelpful individuals like Bruno Goll, the drugstore owner, who denied access to the alarm. It took at least three attempts before someone successfully triggered the alarm, which delayed the response and allowed the fire to grow.

Murphy attributes much of the blame for the fire's escalation to William J. Brown, whom he describes as arrogant. Brown was convinced he was correct and everyone else was wrong, even after his actions led to widespread devastation and loss of life. As Mathias Schaffer's assistant, Brown's responsibility was to relay Schaffer's instructions by activating boxes to signal the fire's location. Initially, Schaffer instructed Brown via a speaking tube to activate Box 342, which sent firefighters to a location several blocks away from the actual fire. Although Schaffer struggled to pinpoint the blaze's exact location, he quickly corrected his mistake and instructed Brown to activate Box 319, indicating the O'Learys' neighborhood. Brown ignored this directive, believing it would add confusion. Consequently, crucial manpower and equipment were misplaced. Firefighters remained unaware of the fire's location until its glow became visible. By then, it was tragically too late.

Initially, the Chief Marshal of the fire department, Robert A. Williams, was held responsible for the rapid spread of the Great Fire. However, an official investigation into his actions and other potential causes of The Great Fire cleared him of any wrongdoing. According to Murphy, Williams expertly managed to establish a defensive perimeter around the blaze, utilizing a small team of local firefighters, outdated equipment, and assistance from local residents. Firefighters fainted on the spot, and others saw their clothes catch fire, not from direct flames, but merely from the extreme heat. Murphy states that they successfully halted the fire's spread in three directions, but lacked the resources to stop it in the direction the wind was blowing.

Throughout much of the night, many people in the fire's path were unaware of the impending danger. Murphy references diaries and other accounts showing that people, fresh from church, casually walked along their streets, barely noticing the fire's glow, as there had been several minor and relatively harmless fires recently. Those observing near the fire, however, felt either terror or fascination. Initially attracting onlookers, the Great Fire soon turned amusement into panic. People began tossing their belongings and children out of windows before jumping themselves to escape the flames. The streets closest to the fire filled with both affluent and impoverished individuals, and families were torn apart in the chaos. Murphy points out that newspapers of the time generally described Chicago's citizens as calm and civilized, helping one another; however, his account suggests a different reality.

One...