True to its name, the street, which began as a Native American trail, eventually leads north to the state of Wisconsin and through Kenosha and Racine towards Milwaukee, though not directly.

Starting with a short section at N. Canal and W. Lake Streets, it begins in earnest at the corner of N. Des Plaines and W. Kinzie Streets and heads northwest for about 40 miles (64 km), eventually following Illinois Route 21 before joining Skokie Highway (U.S. Route 41) in Gurnee, Illinois, which eventually merges at Interstate 94 where Skokie Highway and the Tri-State Tollway split off, continuing to Milwaukee.

The southeastern end of Milwaukee Avenue is the most heavily bicycled stretch of road in Chicago, with cyclists accounting for 22% of all traffic there on a randomly selected day in September.

Milwaukee Avenue runs through the commercial heart of Chicago's vibrant and trendy Wicker Park and Bucktown neighborhoods.

[2] Sections of the movie High Fidelity were filmed in buildings along Milwaukee Avenue, including the Double Door and the fictional record store that is the nexus of the character's lives.

Just northwest of Bucktown, Milwaukee Avenue traverses the heart of Logan Square, Chicago, a gentrifying neighborhood.

The street was once used as part of the route for the Polish Constitution Day Parade as well as Pope John Paul II's 1979 visit to Chicago.

UP-NW - The Union Pacific Northwest Line crosses Milwaukee Avenue at the Jefferson Park Transit Center.