It runs from the Iowa state line at the Mississippi River near the city of Rock Island and runs southeast to the Indiana state line east of Danville, a distance of 220.34 miles (354.60 km).

The highway is officially named after Everett McKinley Dirksen, a Republican representative and senator from Pekin from 1933 to his death in 1969.

After crossing the Iowa state line and the Mississippi River via the I-74 Bridge (through arch span), I-74, as well as US 6, enters the city of Moline.

Near the Quad Cities International Airport, I-74 turns eastward along I-280 while US 6 continues south for a short distance.

Shortly after the Lynch Road interchange, I-74 crosses the Indiana state line.

[citation needed] South of Moline, the bridges over the Rock River were completed some years before they were opened to traffic.

[7] In November 2006, major work was completed on the Upgrade 74 project for the portion of I-74 in the Midwest.

The biggest part of this project was to work on the Murray Baker Bridge, over which I-74 crosses the Illinois River.

The bridge was completely closed to traffic while being partially demolished and reconstructed from April 2 to October 15, 2005.

[9] In late March 2013, a complete $86.6-million (equivalent to $126 million in 2023[10]) reconstruction of the Morton I-74/I-155 interchange, started its beginning phases (Morton, a hub for the two Interstates and the site of facilities for Caterpillar Inc., PepsiCo, and Libby's, is a growing Peoria suburb, across the Illinois River, east of East Peoria and Pekin, in Tazewell County).

[13] In addition to replacing the twin bridges, the scope of the bistate coalition's plan includes updating seven miles (11 km) of I-74 mainline and interchanges from 53rd Street in Davenport to the Avenue of the Cities in Moline.