In 1965, the route's northern terminus was moved from US 22 to US 119.  In 1970, the southern terminus was moved from Johnstown at Washington Street and Clinton Street to Kantner.

Signed in 1941 on its current alignment.  In 1972, the southern terminus was moved from Susquehanna Trail to Chillisquaque.

The southern terminus was moved in 2022 to PA 61 in Sunbury due to the opening of the northern section of the Central Susquehanna Valley Thruway, and the PA 147 designation rerouted onto it and US 15.

On May 19, 2004, the southern terminus was moved from the corner of State Street and Grove Street in Clarks Summit to its current location.  The reason for the move was to create a straighter alignment for trucks that had difficulties turning from PA 407 to US 6/US 11 which resulted in congestion on the latter routes.

In 1970, the eastern terminus was moved to its current location from PA 153 just south of Interstate 80.

In 1946, the northern terminus was moved from US 309 in Sellersville via PA 153, South Perkasie Road, Blooming Glen Road, and PA 113 to its current location.  The southern terminus was moved from Buckingham to Bristol that same year.

In 1975, construction began on the Newtown Bypass and opened in 1977.

In 1940, the section from Morris to Hartfield was paved.  The western terminus was moved from US 15 in Liberty to Morris at PA 84 in 1946.

The western terminus was moved one last time from Morris to PA 44 in 1955.  In 1959, the section from Blackwell to Babb Creek was paved.

The route, surprisingly was still unpaved from Cedar Run to Blackwell until 2001 when it was paved.

The most unusual feature of PA 415 is that it splits at Harveys Lake, with each leg carrying two-way traffic.

Usually the public resists their property being taken for anything related to road construction, except for Steve and Bonnie Wenger, owners of Wen-Crest Farm in Lebanon County.  They donated land to PennDOT to eliminate a dangerous curve on a roadway that had seen terrible accidents.  "Having the landowner on board makes it easier," said Lebanon County transportation coordinator Jon Fitzkee. "We're seeing where we can make some safety improvements."  The project began on April 2, 2010 and was completed in two weeks.

Signed in 1966 on its current alignment

In 1946, the designation was moved to its current location.  In 1977, the southern terminus was moved from PA 77 in Spring Creek to its current location.  It took over for PA 77 from there to Garland.

Signed in 1972 from Interstate 81 in Scranton to its current southern terminus.  In 1976, upon completion of Interstate 380, the northern terminus was moved to its current location.

Frozen groundwater caused the a portion of the roadway in Luzerne County to buckle in January 2014, forcing PennDOT to close the roadway until repairs could be made.

In 1930, the route was paved from PA 241 to Royalton and Ebenezer to Oberlin.  In 1932, the route was paved from Marietta to Bainbridge, Middletown to Highland Street, and from Oberlin to Harrisburg.  In 1935, the northern terminus was moved from 19th Street to its current location.

Construction for an interchange with I-283 and a new alignment for Oberlin Road began in 1968.  It concluded in 1970, and due to the new expressway severing Highland Street, the designation was removed from it between Oberlin Road and Eisenhower Boulevard.

The route travels past perhaps the most famous or infamous island in North America:  Three Mile Island.  During the emergency in 1979, the Pennsylvania State Police shut down the highway in front of the plant from March 28 to April 9.

During the later half of September 2009, crews hauled twin 510-ton generators through Lancaster County en route to their new home at Three Mile Island.  The convoy began traversing PA 441 on September 24 and only moved approximately three miles a day until September 30 when it arrived at the power plant.  Another convoy, this time hauling a used 250-ton generator from the plant, started its trip on April 30, 2010 and stopped that night at the US 30 interchange.  It resumed the trip in the morning of May 2, crawling from that point to PA 462 in Columbia.

In order to mitigate truck traffic through Columbia, PennDOT began construction of a bypass in July 2014.  The $11.8 million highway opened a little after 11 AM on December 17, 2015, and thus the designation was removed from Locus Street and Third Street.

Due to rehabilitation of the bridge over the Amtrak, Norfolk Southern, and Middletown & Hummelstown railroad lines on Ann Street in Middletown which began on March 16, 2020, the decision was made to reroute PA 441 onto and replace Truck PA 441 in its entirety.  When the project finished at the end of May 2020, PA 441 was removed from Union Street between Ann Street and Main Street and placed on its current alignment between those two points.

On March 16, 2020, Ann Street between Harrisburg Pike and Airport Drive was closed to rehabilitate the bridge over the Amtrak, Norfolk Southern, and Middletown & Hummelstown railroad lines.  The $531,403 contract that was awarded to Clearwater Construction, Inc. of Mercer consisted of installing approach slabs for the structure over the railroad lines, replacing the damaged parapet, cleaning bridge joints, repairing the concrete deck, scarifying the bridge deck and placing a 3/8-inch epoxy overlay, updating the traffic signal at PA 230, replacing the existing structure-mounted fencing with standard anti-climb fencing, drainage improvements, curb cut work required by the Americans with Disabilities Act, sidewalk repairs, and new guiderail, signs, and pavement markings.  Once the work was finished at the end of May 2020, the decision was made to reroute PA 441 onto and replace Truck PA 441 in its entirety.

In 1930, the route's western terminus was moved from Harper Tavern to West Jonestown.  In 1936, the western terminus was moved from West Jonestown to its current location.

In 1946, the eastern terminus was moved from Schuylkill Haven to its current location.

Signed in the current location in 1964.