Along a traditional pathway for Native Americans, European settlers, and British troops during colonial times, in the early 20th century, the small valley that became known as Breezewood was a popular stopping place for automobile travelers on the Lincoln Highway, beginning in 1913. Greyhound Lines opened a Post House facility in the town in 1935; it closed in 2004.
In 1940, Breezewood was designated exit 6 on the just-opened Pennsylvania Turnpike. In the 1960s, Breezewood became the junction of the Turnpike and the new Interstate 70. Later renumbered exit 12, it is now exit 161 on the Turnpike following a change to mileage-based exit numbering.