I-380 begins at an interchange with I-80 in the northeastern corner of Tunkhannock Township in Monroe County, heading north as a four-lane freeway.

The road soon crosses into Tobyhanna Township and runs through forested areas in the Pocono Mountains with nearby development, passing west of the Kalahari Resort and Convention Center.

The road passes through part of Pennsylvania State Game Lands Number 127 before it comes to a northbound exit and southbound entrance at PA 423 near Tobyhanna.

[2][4][5] The highway continues through forested areas and curves to the north, passing a northbound weigh station and crossing into Covington Township.

Past this interchange, I-380 curves north into the borough of Moscow and coming to a southbound exit and northbound entrance at PA 690.

The two routes continue north through forested areas in the Moosic Mountains, entering the borough of Dunmore and coming to a bridge over Roaring Brook and a Delaware-Lackawanna Railroad line.

The freeway widens to six lanes and winds through the mountains before it comes to an interchange with Tigue Street, at which point it runs past commercial development.

[8] In 1964, the designation of the proposed road was changed again to I-81E and construction began on the section between the southern terminus at I-80 and exit 3 for PA 940 near Pocono Manor.

[8] On June 20, 1972, the American Association of State Highway Officials (AASHO) approved renumbering I-81E as I-380, along with extending I-84 concurrent with I-380 from Elmhurst Township north to I-81.