It is a regular route for vehicles from Quezon City leading to Manila, as the highway provides access to Quiapo and the University Belt.

The avenue was developed as part of a road plan to connect the government center of Manila in Rizal Park to the proposed new capital on the Diliman Estate.

[3][4] During World War II, its section in Diliman Estate served as a runway of the Quezon Airfield, along with the Manila Circumferential Road (now EDSA).

In place of left turns, the MMDA has constructed U-turn slots 100 to 200 meters (330 to 660 ft) away from the intersections to allow vehicles to reach their destination.

[7] The MMDA would later backpedal on the scheme in 2014 by reverting some intersections along Quezon Avenue to traffic light-signalized ones.