Perkins was born in Boston to a conservative, well-to-do family descended on both sides from the Puritan settlers of New England. The first of several turning points in Perkins' life occurred when she was a student at Mount Holyoke college. One of her professors required her students to visit nearby factories and observe the conditions. She was struck by the fact that the impoverished people she saw there were not lazy or drunk (as she had been told by more conservative members of her family) but were toiling long hours in harsh and dangerous condition. Perkins later recalled that this "opened the door" to her view of social inequities. Upon graduation, she began working in settlement houses.
At one such place, she ran a "girls club" for young women ages 14 to 16. One day, one of the members, Mary Hogan, came home to the settlement house having had her hand chopped off by a candy-dipping machine in the factory where she worked. The management bandaged her and sent her home, without any further treatment or support. Outraged, Perkins took up her cause, seeking medical care and financial compensation. The lack of response from the company and meager amount she was able to secure in donations convinced her that the system that workers existed in had to be reformed. Private charity alone could not protect girls like Mary Hogan.
Perkins continued her work in settlement houses (including Jane Addams' legendary Hull House in Chicago), even as she advanced her education, eventually earning a master's degree in political science from Columbia University in 1910. During her research for her thesis on urban malnutrition, Perkins moved into the neighborhood known as "Hell's Kitchen." Rather than just observe, she fought for the hungry, destitute people around her, appealing to the politicians of famously corrupt Tammany Hall for immediate relief. She later recalled that her success in doing this convinced her that it was imperative to work within the system. Even if the Tammany bosses were motivated by a desire for votes, they greased the wheels and delivered.
Another major turning point in Perkins' life came on March 25, 1911, when she was having tea with a friend down the street from the Triangle Shirtwaist Factory. Inside the factory, workers-- mostly women and girls-were working making clothing when a fire broke out. The blaze spread quickly as the panicked workers tried to escape. Although a few managed to cross over to another building on the top floor, most of the others were trapped. There was only one fire escape, which soon collapsed, and the elevators didn't work. Perkins later recalled what she saw when she and her friend got up and went to see what was happening: "Just about that time they began to jump. It was the most horrible sight."
At least 146 young women burned to death or died on the sidewalk that day, creating a public cry of outrage. An investigation revealed that owners regularly kept the doors locked to keep labor organizers out, that no fire drills had been conducted and that the oily sewing machines were squeezed close together while flammable scraps piled up around them.