Holbrook is an important trade center for northeastern Arizona. Its Location on historic Route 66 and on Interstate 40 at the junction of four major highways, between the Apache Sitgreaves National Forest to the south and the Navajo and Hopi Indian Reservations to the north, makes tourism important to the local economy.

Government employment is also significant because Holbrook is the Navajo County seat and the site of various state and federal field offices.  All of Navajo County is a designated Enterprise Zone.

The Cholla Power Plant, Arizona Public Service's largest coal-fired generating station, is located just outside of Holbrook and employs approximately 250 workers.