Huntington Drive was the major route between Los Angeles and Pasadena in the early 1900s until the opening of the Arroyo Seco Parkway.

The median contained the Monrovia–Glendora Line of the Pacific Electric Railway which was owned by the street's namesake, Henry Huntington.

In the 1930s, traveling on Huntington would have drove you by the Cawston Ostrich Farm in South Pasadena and in Monrovia a hot dog stand, the first restaurant opened by the McDonald brothers who would later create the fast-food restaurant McDonald's.

Huntington Drive between Soto Street and Fair Oaks Avenue was the original alignment of US 66 from 1926 until around 1936 when it was re-routed to eventually the Arroyo Seco Parkway.

Between Colorado Boulevard east to the Irwindale city limit it was signed as US 66 until it was decommissioned.