US 60 merges onto the James River Freeway where it has a brief concurrency with US 160 and Route 13.

Between Springfield and Willow Springs, US 60 passes through various communities, most of them are mainly accessible by exits.

It passes through Rogersville and Fordland before leaving Springfield metropolitan area.

At this point, US 60 no longer parallels the BNSF railway tracks as it heads down to West Plains as well.

US 60 passes through Mountain View where the divided highway briefly ends, While passing through Mountain View, US 60 has left turn lanes and has a concurrency with Route 17.

Next, US 60 has a concurrency with US 67 until it enters Poplar Bluff as it leaves the Ozark Plateau.

After leaving Poplar Bluff, US 60 intersects Route 51 north of Fisk.

Next, US 60 passes through Dexter then intersects Route 114 east of Morehouse.

US 60 will leave Missouri crossing after the Cairo Mississippi River Bridge along with US 62 into Illinois.

[citation needed] On May 17, 1946, William Jefferson Blythe, Jr., the biological father of Bill Clinton, died on US 60 in a car accident after he was tossed out of his vehicle and drowned in a ditch.

The Missouri Department of Transportation (MoDOT) completed the process of upgrading 59 miles (95 km) of US 60 from Willow Springs to Van Buren to a four-lane highway (two lanes in each direction) on July 9, 2010, marking the completion of a continuous four-lane highway from Republic to Charleston, a total of approximately 240 miles (390 km).

[citation needed] The portion of US 60 from Springfield to Sikeston was a consideration for the then proposed later cancelled Interstate 66 extension to follow.