US 68 passes near or through Reidland, Aurora, Cadiz, Hopkinsville, Elkton, Russellville, Auburn, Bowling Green, Glasgow, Edmonton, Greensburg, Campbellsville, Lebanon, Perryville, Harrodsburg, Lexington, Paris, and Maysville.

The Jefferson Davis State Historic Site is located along the highway, approximately 9 miles (14 km) east of Hopkinsville at the small town of Fairview.

The long-term goal is to widen and make safer the entire US 68 corridor through Kentucky as part of the Heartland Parkway project.

This was accelerated, following a devastating collision of the cargo vessel MV Delta Mariner with Eggner Ferry Bridge in January 2012.

US 52 leaves the concurrency at Ripley, at which point US 68 and US 62 head north for 5.3 miles (8.5 km) as a generally rural two-lane highway.

Shortly before reaching Interstate 70, it becomes a four-lane expressway, bypassing Springfield before transitioning back to a rural two-lane road as it approaches Urbana.

Near Redoak in Brown County, the designation "Brigadier General Charles Young Memorial Historical Corridor"[4] leaves the US 62/US 68 concurrency and joins US 68 solely at the routes' junction.

US 68 previously ran to Toledo, Ohio, terminating at the west approach to the Anthony Wayne Bridge south of downtown, but the Toledo-Findlay segment was decommissioned in the 1950s.

In September 2013, the Clark County-Springfield Transportation Coordinating Committee (TCC) ranked the US 40/SR 4/Upper Valley Pike intersection as the most hazardous in the county, based on 2010-2012 crash data.

[20][21] Because the road design over the years had played a significant factor in the high number of crashes in the area, the TCC conducted a study; in February 2006 it recommended reconfiguring the US 68 interchange and altering nearby traffic patterns.

However, the TCC soon rejected ODOT's money, concluding that even its recommended fix would not be enough to solve the area road network's underlying problems.