The current confluence of the Mississippi and the Missouri rivers is just south of one of these neighboring villages, Hartford.

Wood River is bordered to the northwest by East Alton, to the north by Rosewood Heights, to the northeast by Bethalto, to the southeast by Roxana, to the south by Hartford, and to the southwest, across the Mississippi River, by West Alton, Missouri.

Illinois Route 3 passes through the west side of the city, leading north 5 miles (8 km) to the north side of Alton and south 18 miles (29 km) to East St. Louis.

Illinois Route 255, a four-lane limited-access highway, passes through the east side of Wood River, leading northwest 10 miles (16 km) to Godfrey and south 15 miles (24 km) to Collinsville.

Amtrak's Texas Eagle as well as its Lincoln Service pass through Wood River but do not stop in the small city.

St. Louis Regional Airport is 3 miles (5 km) northeast of Wood River in Bethalto, while the nearest commercial flights are available at St. Louis Lambert International Airport, 25 miles (40 km) to the west in Missouri.