Palmerston Boulevard was originally part of a subdivision called Seaton Square, laid out in 1854, though most of the houses weren't built until between 1903 and 1910. Developed as an upper-middle-class street of mostly detached homes, it attracted doctors, professors, and former Toronto mayors.

The street's stone gate posts at Bloor and College Streets are a remnant of its early years as part of the Seaton Village development, suggesting the entrance to a private rural estate despite always being within the city limits. The cast-iron globe-topped street lamps lining the boulevard date from the period the street was developed — described by one authority on historic street lighting as "an authentic street lighting installation — an electrical time capsule."

Notable residents over the years have included George Weston, whose bakery would start a family retail legacy, as well as two former Toronto mayors. The acorn sign at Palmerston and Harbord marks the quieter southern stretch of the boulevard, just below its midpoint between College and Bloor.