After passing through Mayfield in Graves County it heads directly north into Paducah as a four-lane highway.

In Graves County US 45 travels northeast and passes through the communities of Water Valley and Wingo.

US 45 crosses the Ohio River via the Brookport Bridge into Illinois 51.880 miles (83.493 km) from the Tennessee state line.

It carries this concurrency for 2.860 miles (4.603 km) and ends at a junction with US 45 at exit 25 of the parkway north of Mayfield.

Since the former Purchase Parkway has been re-designated I-69, US 45 Bypass signs have been removed from the I-69 concurrency, and the north interchange with US 45.