The 49-year-old had been in charge for just over two years, but the loss was Preston’s sixth in seven league games, leaving them second bottom of the Championship.
The club highlighted their £15million summer spending, saying results had been unacceptable.
“Preston North End Football Club have today taken the decision to part company with Paul Heckingbottom as First Team Football Manager,” the statement read.
“Football is a results business and despite significant investment in the playing squad since Paul joined, the results during 2026 and the start of this current campaign have not been acceptable.
“Paul leaves us with our thanks and best wishes. His professionalism and work ethic during his time with us have been second to none.
“As a result of this decision Stuart McCall has also left the Club today. We similarly thank Stuart for his contribution over the last two years and wish him all the best for the future.
“We will now look to appoint a new manager as soon as possible but until such time as we do Jason Euell will take charge of first team matters on an interim basis.”