Most were departing Thursday from Buckley Air Force Base in Aurora. Officials say they cannot be specific about where they are going because of security rules.
They are members of the 140th Wing, which has an F-16 fighter squadron as well as maintenance, medical and mission support groups. The wing is based at Buckley.
In a written statement, the wing said the F-16s will support "national security and stability" in the Mideast.
Officials declined to say how many aircraft will go.
The Colorado F-16s are sometimes called on by the North American Aerospace Defense Command to intercept commercial aircraft that fly into restricted areas or whose pilots don't respond to traffic controllers.