In 1932, the route between Ohio and PA 551 and New Galilee and Darlington was paved.  In 1936, the eastern terminus was moved from Darlington to the current location.  Also that year, the route from Koppel to Ellwood City opened.

In 1930, the section from Braeburn Road to Freeport was paved.  In 1932, the section from PA 56 to Braeburn Road was paved.

In 1941, the route was moved from Neupert Road, Water Street, and Saxonburg Road between Hannahstown and Butler to its current alignment.  In 1946, the southern terminus was moved to its current location from PA 56 in Weinels Crossroads.

Time was beginning to take its toll on the former Garvers Ferry Bridge, which previously carried the route over the Allegheny River, by the 1950s.  That bridge opened in 1888 but was closed on May 21, 1957 when inspectors discovered so much rust that they were unsure how it was still standing.  Emergency repairs took place then but a flood in January 1959 sent a barge crashing into one of the piers which caused a section of the bridge to fall into the river.  The section was raised back into place so traffic could continue to cross the river while its replacement could be built which was completed in 1965.

In 1972, the northern terminus was moved from Main Street in Butler to its current location.

By the 21st Century, Freeport Bridge was beginning to follow the same path as the one it replaced and even forcing the weight limit on the Freeport Bridge to drop to three-tons.  Emergency steel repairs took place between 2006 and 2007 which totaled $5 million and allowed the weight limit to be raised to 40 tons.  In the wake of the Interstate 35W bridge collapse in Minneapolis in 2007, PennDOT released condition ratings for the state's 54 steel deck truss bridges, which included the Freeport Bridge, on August 14 of that year.  The information was not up-to-date as it still indicated that the span had "serious" deterioration of its superstructure, and it had a "poor" deck and substructure contrary to the repairs that had just been made.

A complete rehabilitation and strengthening project began on July 12, 2010 on the Freeport Bridge.  The project not only included rehabilitation and redecking of the span, but also involved reconfiguring the northern end where it connects to Freeport Road.  The previous ramp configuration at that end which comprised 13 intersections and three weave areas was replaced with an intersection.  Previously, PA 356 southbound descended towards Freeport Road, but split off to the left; however, PA 356 northbound joined Freeport Road and entered Freeport on a roadway which paralleled Second Street and then joined Buffalo Street to cross Buffalo Creek.  The $63 million project concluded in October 2013.

In 1954, it was moved back to Greenville.  In 1964, the eastern terminus was moved from Greenville to its current location.

Signed in 1946.

In 1950, the southern terminus was moved from PA 23/PA 83 in Valley Forge Park to Port Kennedy.

In 1961, the southern terminus was moved from Port Kennedy to US 202.  In 1967, the southern terminus was moved from US 30 in Devon to US 202 in King of Prussia via the US 422 expressway.

In 1985, the southern terminus was moved from US 202 in King of Prussia to the current location.

Construction began in October 2013 on improving the US 422 interchange.  The $16.8 million interchange project will also include realigning the existing on-ramp to US 422 eastbound, construction of new retaining and sound walls, widening PA 363 through the Audubon Road intersection, widening Audubon Road, rehabilitating the PA 363 bridge over US 422, construction of a sidewalk on PA 363, new traffic signals, and curb ramps.

Signed on the current PA 144 alignment from State Camp to Renovo from 1928 to 1930 as well as from Orviston to Beech Creek.  In 1930 the designation was moved to the alignment above and paved in 1932.

Construction began on the Tarentum Bridge and its approaches in 1950 and it was completed in 1952 as a toll bridge.

In 1961, the western terminus was moved from Seventh Street in New Kensington to West Seventh Avenue in Tarentum via Stevenson Boulevard.  A year after, the tolls were removed from the Tarentum Bridge over the Allegheny.  In 1970, construction began on the PA 366/PA 380 cloverleaf which was completed in 1972.

The western terminus was moved, once again, to its current location at the Allegheny Valley Expressway in 1985.  Work to widen the route from Freeport Road to the Tarentum Bridge began in 2005 and was completed in 2007.

The Parnassus Triangle in New Kensington, where Industrial Boulevard and Logan's Ferry Road intersected, was a dangerous junction due to limited sight lines and narrow roadways.  Construction began in Spring 2009 to rectify those issues as well as widen PA 366 to four lanes between that point and PA 56.  Work also included replacing the bridge over Little Pucketa Creek and installing new traffic signals at two intersections.  The $8.1 million project was to be completed in July 2010, but due to inclusion of a barrier that was not in the original plans, work did not finish until October 6.

Another junction reconstruction project in the New Kensington area began on April 16, 2014 at the opposite end of the multiplex with PA 56.  The $2.8 million project will replace the bridge that carries westbound traffic over PA 56 which will be 55-feet-wide and two-feet higher to comply with new design standards.  May 2015 is the estimated completion date for work.

In 1934, the section between Parker and Perryville Road was under construction.  In 1935, that section opened and the designation moved off Perryville Road.

In 1967, the eastern terminus was moved from PA 68 in Silgo to its current location.

In 1946, the eastern terminus moved from PA 570 in Preston Park to then PA 90, now PA 191.

In 1950, the sections from Niagara to Turner Road and Rileyville to Holgate Road was paved.  In 1954, the western terminus was moved from US 11 in New Milford via Great Bend Turnpike and the current PA 848 alignment.

The eastern terminus moved from Christiana to Coatesville in 1946.

Construction began in 1967 on the Norman Wood Bridge over the Susquehanna River and opened in 1968.  With that being completed, the western terminus was moved from McCalls Ferry to its current location.

During an inspection on September 28, 2015, an eight-foot-long crack was discovered in one of the support beams of the Norman Wood Bridge.  The crossing was immediately closed to traffic.  Repair work began on October 5 and by October 9, it was determined that the damage was not as severe as originally thought.  Temporary traffic signals were installed on either end of the bridge, and one lane of traffic was allowed to utilize the eastbound lane of the bridge safely with a five ton weight limit starting on October 16.  The work entailed jacking the bridge up from the girder, drilling holes in the metal to stop the crack from enlarging, and then affixing two large 14-foot-high-by-five-foot-wide plates on top of each other over the crack.  The weight limit was removed on November 2 and the bridge reopened to two-way traffic the following day.

SR 0376 is currently assigned to Interstate 376.

Construction from West Broad Street to US 22 began in 1966 and finished in 1968.  At that time, the segment received the Interstate 378 designation.

Street lights were included in the project at the behest of the City of Bethlehem and Bethlehem Steel.  Outside of interchanges, there wouldn't be much illumination but the city and company wanted extra lighting.  In order to get the deal done, the city agreed to split the costs for the extra lighting with the Department of Highways.

The PA 378 designation was signed in 1971 after I-378 was decommissioned.  In 1974, the designation replaced PA 191 from Center Valley to Third Street in Bethlehem.

By the 2010s, the street lights on the expressway segment began to malfunction as the infrastructure for them began to fail.  The lights were eventually shut off around 2015 with the city only receiving a handful of complaints.  Replacing the 300 metal poles and their underground wiring would be around $3 million according to Michael Alkhal, Bethlehem's director of public works and Ron Young, spokesperson for PennDOT.  Young said the department isn't interested in spending that when the extra lights weren't needed to begin with, and Alkhal said it is hard to justify spending that money.

On August 9, 2019, the Lehigh Valley Transportation study released its first draft of its long-range transportation plan.  It projected spending $117.3 million to rehabilitate the Hill to Hill Bridge in Bethlehem, widening it without adding lanes, between 2025 and 2027.  Also included would be improving the entire expressway between Main Street and US 22 for $19.9 million and improving three miles between Colesville Road and Brighton Street for $13.4 million.

In 1930, the route was paved from Perrysville to PA 80.

In 1961, the western terminus was moved from the intersection with its parent route at Penn Avenue in Wilkinsburg to the Fort Pitt Bridge approaches at Point State Park in downtown Pittsburgh.  In 1969, work started on a new alignment from Crestview Drive to PA 66 that opened in 1970.

In 1970, construction began on the PA 380/PA 366 cloverleaf, which finished in 1972.  Originally ended at the interchange of I-279 and I-376 until 1985.  That year the route was removed from Liberty Avenue and Seventh Street in downtown Pittsburgh and the western terminus moved to its current location.

Signed in 1961 on its current alignment.

In 1936, the route was moved from the current PA 65 alignment between New Brighton and New Castle to its current location.

In 1940, the section from Frew Mill Road to PA 168 was improved.  In 1941, the section from US 442 to PA 108 was paved.  In 1946, the section from PA 108 to PA 168 was paved. 

In 1940, the section from the Monroe County line to Roemersville was paved.  In 1948, the section in Roemersville was paved.  In 1949, the section from Roemersville to north of Promised Land State Park was paved.

Signed in the current location in 1961.