As with most primary Interstates that end in a five, it is a major cross-country, north–south route, connecting the Gulf of Mexico to the Great Lakes.

The highway travels from LaPlace, Louisiana, at I-10 to Chicago, Illinois, at U.S. Route 41 (US 41, Lake Shore Drive), at McCormick Place.

The major cities that I-55 connects to are (from south to north) New Orleans, Louisiana; Jackson, Mississippi; Memphis, Tennessee; St. Louis, Missouri; and Chicago, Illinois.

During the rest of the 1960s, I-55 was built in portions throughout Illinois, eventually connecting St. Louis to Chicago, where it became the fourth direct route between them.

Approximately a third of the distance consists of the Manchac Swamp Bridge, a nearly 23-mile (37 km) causeway, often cited as the third-longest viaduct in the world.

The western portion of this highway, which passes through an industrialized section of the city, contains numerous low-clearance bridges and also a very tight 270-degree cloverleaf turn northbound at Crump Boulevard.

[3] I-55/US 61/US 63 continues north through Crittenden County through rural farms of the Arkansas delta, including an interchange with I-555/US 63 in Turrell.

It runs from the Poplar Street Bridge in East St. Louis to US 41 in Chicago, passing around the state capital of Springfield and the metro area of Bloomington–Normal.

Finally, in the Chicago area between the I-80 interchange near Joliet and I-55's eastern terminus at US 41 (Lake Shore Drive) in Chicago, the expressway is referred to as the Adlai E. Stevenson Expressway (previously called the Southwest Expressway) in honor of former Illinois governor Adlai E. Stevenson II, who was a two-time Democratic nominee for President of the United States and also the US Ambassador to the United Nations under Presidents John F. Kennedy and Lyndon B. Johnson.