At Columbia in a section known as "Malfunction Junction", it connects with I-20 to Augusta and Florence and I-126 toward the downtown area; it then goes south over the Saluda River and into Lexington County for the second of eventually four times along its course.

South of Cayce, the Interstate goes up and down a few very long hills before reaching the outskirts of Orangeburg and I-95 to Savannah and Florence.

As the Interstate curves through the peninsula formed by the Ashley and Cooper rivers, it connects with I-526 to Savannah and Mount Pleasant.

The South Carolina Department of Transportation (SCDOT) operates and maintains one welcome center and seven rest areas along I-26.

[3] The South Carolina Department of Public Safety (SCDPS) and State Transport Police (STP) operates and maintains three truck inspection/weigh stations.

[4][5] Construction of I-26 began in 1957 in the Columbia area with the nine-mile (14 km) section from the Broad River to near Irmo.

The highway was largely completed from Columbia to North Charleston by 1964; the section from Aviation Avenue to the highway's terminus at US 17 in downtown Charleston progressed more slowly due to land takings for the right-of-way and numerous bridges and viaducts that had to be built.

Starting in 2019 or 2020, a long stretch of I-26 northwest of Columbia will begin widening construction from four to six lanes from SC 202 at Little Mountain to US 76/US 176 at Irmo.

[11] On November 19, 2016, construction began in Charleston to demolish, reconfigure, and replace exits 217 and 218, related to a new access road to the Hugh K. Leatherman Sr. Terminal; the interchange was opened on February 23, 2021.

[15] On July 6, 2023, a tractor trailer pulling an excavator hit a bridge carrying Bachman Chapel Road over I-26 in Newberry when it was too tall to clear it.

[18] In Columbia, work has begun on the "Carolina Crossroads" project to redo improve the Interstate corridors in the city.

Bidding for at least a part of the 70-mile-long (110 km) project is expected to begin by the end of 2023 with construction tentatively scheduled to start in the middle of 2024.