Construction began on the alignment from PA 313 to Haycock Run.  The reason being was the creation of the Nockamixon State Park Lake neccessitated moving the alignment.  In 1973, the new segment opened and the designation was rerouted.

It takes a really big snow storm to close roads and that is exactly what hit on February 9, 2010.  Governor Rendell took proactive measures and closed PA 581 at 2:00 PM the following day.  In a press release he stated, "For your safety, do not drive.  You will risk your life and, potentially, the lives of others if you get stuck on highways or any road.  The National Weather Service issued blizzard warnings for several counties in Pennsylvania and visibility is at or near zero."  The Harrisburg Expressway reopened on February 11.

Normally when a bridge needs replaced it is demolished and a new one built in its place, but PennDOT tried out a new technique in 2015.  On May 28, PennDOT Secretary Leslie S. Richards announced that replacement of the 60-year-old 10th Street overpass in Lemoyne would begin, but instead of the traditional build-demolition plan that would take at least a year, it would be accomplished in only a few weekends.  "Normally, this kind of bridge rehabilitation project would have taken as long as a year and a half with full-time traffic disruptions," Richards said at an event in the staging yard where the pre-fabricated bridge elements were built. "But forcing drivers to endure that level of inconvenience on such a busy highway for that long is not the way we want to do business."  Construction on the new bridge sections began in 2014 nearby in a yard off Lowther Street, bolted together to make sure they would fit in the space of the former bridge, and then separated into three or four sections each weighting 120 to 130 tons to be transported to the site.  A special 650-ton crane from Austria was brought in to lift the giant sections into place.  The $2.7 million project began on the weekend of June 6 with the closure and demolition of the eastbound lanes, with the westbound lanes closed and demolished the following weekend.  After the sections were placed, the contractor resurfaced both eastbound and westbound bridge decks with a latex-modified concrete overlay which was completed during the weekend of July 18.

There was talk of this route being upgraded to an Interstate designation before the extension to Interstate 81, and in fact, PennDOT attempted to do that very thing in 1994.  On June 9, 1994, the American Association of State Highway and Transportation Officials had a meeting  with PennDOT to address issues with PA 581.  There were three of note: the relatively short ramp to Interstate 81 southbound, improving the merging/diverging movements at US 15, and improving the geometrics and waves at the Interstate 83 interchange.  While AASHTO identified some benefit of a loop at this location, they did not approve an Interstate 581 designation.