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Just as technology caused the National Road to decline, it also led to its revival with the invention of the automobile in the early 20th century. As "motor touring" became a popular pastime the need for improved roads began to grow. Many early wagon and coach roads such as the National Road were revived into smoothly paved automobile roads. The Federal Highway Act of 1921 established a program of federal aid to encourage the states to build "an adequate and connected system of highways, interstate in character." By the mid 1920's the grid system of numbering highways was in place, thus creating US Route 40 out of the ashes of the National Road.

Due to the increased automobile traffic on US Route 40 a whole new network of businesses grew to aid the 20th century traveler. The stage taverns and wagon stands were replaced by hotels, motels, restaurants and diners. The service station replaced the livery stables and blacksmith shops. Some of the National Road era buildings regained new life as restaurants, tourist homes, antique shops and museums. Route 40 served as a major east-west artery until the Federal-Aid Highway Act of 1956 created the interstate system as we know it today. With the opening of the interstates much traffic was diverted away.