The Big Muddy joins the Mississippi River in Jackson County near the La Rue-Pine Hills Ecological Area and less than 1 mile (1.6 km) south of Grand Tower Island.

During the melting of the Wisconsinan glacier, the Mississippi River flood plain was filled with rushing meltwater in summer.

When the Big Muddy flooded, the water covered the flat bottom of the ancient lake bed for miles either direction from the meandering channel.

The steep Illinoian hills are suddenly truncated where they meet the flat bottom of the Wisconsinan Era lake bed.

The first coal mine in Illinois is believed to have been opened in 1810 on the banks of the Big Muddy in Jackson County.

The Big Muddy cuts through the Shawnee Hills south of Murphysboro near the confluence with its smaller tributary, Kinkaid Creek.

From there, it runs southward roughly twenty miles and meets the Mississippi directly south of Grand Tower.

Near its mouth, a small portion of the Big Muddy acts as the dividing line between Jackson and Union counties.