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Prior to receiving its current designation, the planned corridor of I-380 had several other designations. When the initial numbers for the Interstate System were assigned in 1957, the Scranton–New York route (including the current I-380) was designated I-82.^[1] This changed the next year, and the Scranton-Stroudsburg connection became I-81S, a spur of I-81.^[2]

In 1961, construction began on a short section of the route between what is now Exit 2 for PA 435 (then part of U.S. Route 611) and its northern terminus at I-81 outside of Scranton.^[3] This section was opened in 1962 as part of US 611.^[3] In 1964, the designation of the proposed road was changed again to Interstate 81E and construction began on the section between the southern terminus at Interstate 80 and Exit 3 for PA 940 near Pocono Manor.^[3] This section was built at the same time as the connecting section of I-80 and both opened in 1965.^[3]

In December 1966, it was announced bids were to occur soon to build a portion of the highway between Pocono Manor in Tobyhanna Township and Coolbaugh Township.^[4] On December 30, 1966, bids were made to build a section of I-81E in Coolbaugh and Tobyhanna townships.^[5] In February 1967, construction was planned for a section of highway in Coolbaugh Township between Tobyhanna and the border with Lackawanna County.^[6] On April 21, 1967, the state announced bidding would take place to build a section of I-81E in Monroe County on May 12.^[7] The state announced on June 9, 1967 that bidding would take place on June 23 to construct a section of the highway in Covington Township.^[8] The section of I-81E between the PA 940 interchange in Pocono Manor and US 611/PA 423 at Tobyhanna was projected to open in fall 1968, and construction of the highway between Tobyhanna and Elmhurst was underway by 1968.^[9][10]

On November 21, 1969, the section of I-81E between PA 507 in Gouldsboro and PA 307 in Daleville opened to traffic.^[11] By 1970, the road between PA 307 in Daleville and US 611 southeast of Dunmore was under design.^[12]

In 1967, construction on the road was restarted on a 17-mile (27 km) southern section from PA 940 to PA 423 and PA 507 to the Dorantown Road overpass, and, in 1968, was expanded to the sections from PA 423 to PA 507 and the Dorantown Road overpass to PA 307.^[3] This section opened in 1970 with US 611 multiplexed onto the portion between Exit 8 (now PA 611) and Exit 13 (PA 507) adjacent to Gouldsboro State Park.^[3]

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 north to I-81.^[13] The renumbering was done in order to avoid the confusion of I-81E with the connecting I-80 and I-81 designations. The new I-380 designation and extended I-84 would take affect in spring 1973, with the new signs to be installed by June of that year.^[14] In 1973, the northern section was upgraded to Interstate standards.^[3] In 1974 and 1975, work commenced on the final sections from PA 307 to the Shutters Road underpass and Shutters Road to PA 435, respectively.^[3] This included an interchange with Interstate 84 was opened to traffic in 1976 as an east-west highway with mileage-based exit numbers.^[3] These mileage-based numbers were scrapped by 1977 and replaced with eight sequential numbers beginning in Scranton. Mileage-based exit numbers were revived in 2001 when the Pennsylvania Department of Transportation renumbered its Interstate System exit numbers. I-380 was redesignated as a north–south highway so that its exit numbers would commence from I-80 in the south.^[3]