Crab Orchard National Wildlife Refuge is located in the southern portion of Illinois, with lands in Williamson, Jackson, and Union counties. The Refuge headquarters building is located about five miles west of Marion, Illinois, and about five miles south of Herrin, Illinois, of State Route 148 into Pigeon Creek Road.

To get to the Refuge Headquarters building from I-57, take exit 54 B onto IL-13W toward Carbondale for 3.6 miles until you reach the IL-148 intersection. At this intersection, turn left onto IL-148 and travel South 1.6 miles until you reach the Pigeon Creek Road intersection, in this intersection turn right and then turn left onto Headquarters Road. To get to the Refuge Headquarters building from I-24, merge onto I-57 N via exit 44B for 1.3 miles until you reach exit 45, IL-148. Take IL-148 North for 7.7 miles until you reach the Pigeon Creek Road intersection, in this intersection turn left and then turn left onto Headquarters Road.