The freeway has a dumbbell interchange with Vandehei Street before leaving the city of Cheyenne and passing through the unincorporated area of Ranchettes. I-25 has an interchange with WYO 211 (Horse Creek Road) before US 85 splits to the northeast.
I-25 continues north along the western edge of the city of Cheyenne and along the eastern edge of Francis E. Warren Air Force Base, which is served by the next three interchanges. The highway has a five-ramp partial cloverleaf interchange with Missile Drive, crosses over a BNSF rail yard, and has a diamond interchange with Randall Road, which leads to Pershing Boulevard.