Initial construction work began in the early 1960s, and for many years, only two miles (3.2 km) of the highway was open to traffic.

Initially heading northwest, the Interstate immediately passes under State Route 169 (SR 169, Middlebrook Pike) without an interchange.

It then veers northeast into the southern fringes of Dutch Valley, running along the northern base of Sharp's Ridge.

[1] The highway then gradually shifts south and, a few miles later, crosses another Norfolk Southern mainline and US 11W (Rutledge Pike) without intersecting this route.

[15][16][17] On December 4, 1964, what is now the interchange between I-40/I-75 and a short segment of I-640 extending north to SR 169 (Middlebrook Pike) was opened to traffic, providing access between both routes to local motorists.

[20][21] The remainder of I-640 was initially delayed by disputes over its final alignment and disagreements between the city of Knoxville and the state over the improvement of nearby surface streets.

[27] Work on the final section, located between US 441 and the eastern terminus with I-40, began in July 1979 and was opened to traffic on December 21, 1981.

[35][36] Final signage, lighting, and landscaping work was completed in April 1982,[27] and the flyover ramp from I-40 eastbound onto I-640 at the eastern terminus opened on July 1, 1983.

[37] Then-Governor Lamar Alexander officially opened both sections by leading a walk along their entire lengths dressed in his red plaid shirt that he famously wore during both of his campaigns for governor.

During this time, the ramps at both termini of I-640 carrying this traffic were temporarily widened to three lanes to facilitate the extra volume.

[48] The deterioration of the underlying concrete had made this stretch of roadway susceptible to forming cracks and potholes, and had been patched and repaired multiple times.

[47] This project was initially slated to be finished by November 30, 2023, but experienced multiple delays resulting from higher-than-expected concrete grades in the surface and potholes on bridges.

[49][50][51] On August 26, 2024, all lanes were reopened to traffic, and final ramp and shoulder paving work was completed over the next few weeks.