It travels east–west through the state for 189 miles (304 km) passing by the major towns and cities of Huntington, Charleston, Beckley, and Lewisburg.

From the final crossing of the Kanawha River east of Charleston to their split at exit 40 south of Beckley, the two Interstates are tolled, forming a part of the West Virginia Turnpike.

Two steel-girder bridges were completed over the Big Sandy River connecting Kentucky to West Virginia.

Shanklin reversed his decision soon after and stated that Charleston can adjust to the impact and that it will eventually become a "great thing".

The long planned Interstates through West Virginia were either to run directly through the city center or to skirt it.

The plan was to bring I-64 through the Triangle District, just west of the downtown center, an urban blight,[citation needed] where many of the city's Black population lived.

Home to the city's highest crime rates where shootings daily were common; it was referred to as the "Red Light District".

They called the highway routing foolish because it wanted to make Charleston just another exit on an endless ribbon of concrete and that it was racist because the Black population would bear the brunt of the relocation.

[citation needed] Federal transportation secretary John A. Volpe stalled for months at the decision on the routing of I-64 through Charleston.

[citation needed] Construction began in September 1971, cutting away parts of 14 mountains and demolishing over 1,000 homes on the south banks of the Kanawha River.

From that point, I-64 was concurrent with the northern portion of an upgraded West Virginia Turnpike to reach the Charleston area.

[2] The final segment of I-64 to be completed was between Sam Black Church and the West Virginia Turnpike near Beckley.

It has some extremely rugged terrain, with one segment boasting a seven-percent grade downhill eastbound for seven miles (11 km) at Sandstone Mountain.

Even with careful adherence to reduced speeds for truckers, the journey from Charleston to Lewisburg is far quicker and far safer on I-64 than the older routing via US 60, much of which winds through the mountains as the Midland Trail, a two-lane scenic byway, passing through hamlets such as Rainelle and Ansted.

Exit 20, the main road to the Huntington Mall and its associated developments along with US 60, was originally constructed as a diamond interchange that served Ona and US 60.

Exit 20B was kept, for the most part, in its current position with a left turn lane added that allowed it to serve the east end of Huntington Mall, Melody Farm Road, and US 60.

The WV 10/Hale Greer Boulevard crossings were approaching 40 years of life and decayed to the point where regular maintenance was needed.

A three-by-three-foot (0.91 by 0.91 m) segment of the westbound bridge collapsed in early 2002 after a harsh winter, for example, and this only highlighted the problems being experienced on the original I-64 spans.

The bridge, built in 1961, utilized steel girders that had become deteriorated over the years and were replaced with prestressed concrete beams.

[7] As of 2021[update], the third Kanawha River crossing at Nitro is currently under reconstruction in a project very similar to the South Charleston expansion.

The combined spans will carry six throughlanes, three in each direction, with two auxiliary lanes servicing the Nitro and St. Albans exits on each side of the bridge.

[8][needs update] Other notable recent projects: The state's long-term construction forecast, for a six-lane Interstate from milepost 6 at West Huntington to Charleston and bridge replacements west of milepost 6 to the Kentucky state line, will take 30 years to complete at present funding levels and cost more than $325 million.

The portion from the Charleston city limits to the Kentucky state line is signed as the "Cecil H. Underwood Freeway", named after the 25th and 32nd governor of West Virginia.