It serves the extreme southern region of the state, commonly called Little Egypt or the Illinois Ozarks.

IL 146 generally follows a land route of the Trail of Tears, a trail taken by bands of approximately 9,000 Cherokee who were forced to march through southern Illinois from November 1838 until January 1839 as part of a U.S. government mandated relocation.

In 2006, the state of Illinois designated IL 146 as a historic highway and route of the Trail of Tears.

IL 146 passes through an area of Illinois noted for scenic beauty and significant tourist visitation.

State-operated parks and recreation areas on or adjacent to IL 146 include, from west to east: The city of Jonesboro was the site of an open-air debate between Abraham Lincoln and Stephen Douglas in 1858.