Wane, who previously coached Wigan, was appointed in February 2020, taking charge of his first competitive match in June 2021 before leading England when they hosted the Rugby League World Cup the following year.
England lost to Samoa in the semi-finals, and Wane then won a test series over Tonga in 2023 and then against Samoa the following year, before suffering an Ashes whitewash against Australia in November last year.
"It has been the honour of my life to coach England Rugby League over the last six years but after careful reflection I believe the time is right to step aside and allow the programme to move forward into its next chapter," Wane said in an RFL statement.
"I wish everyone involved with England Rugby League the best going forward and for the World Cup later this year."
The 2026 Rugby League World Cup will be hosted by Australia, Papua New Guinea and New Zealand in October-November.
England will face Tonga in Perth in their opening match on October 17th, then take on France a week later before completing the group stage against Papua New Guinea in New South Wales.