The 61-year-old took over the position in June 2020 but will leave after 18 months in charge after some Premier League clubs expressed their discontent with the way Newcastle United’s Saudi-Arabia backed takeover was handled.
Newcastle were taken over by Saudi Arabia’s Public Investment Fund last month in a £305m deal, making them one of the richest clubs in the world overnight.
More than half of Premier League chairmen reportedly made Hoffman the subject of an unofficial vote of confidence last week.
"The Premier League is grateful to Gary for his committed service," a statement from the Premier League on Wednesday read.
"He has led the League during the most challenging period in its history and leaves it in a stronger position than ever.
"The process of appointing a new Chair will begin immediately."
Hoffman added: "It has been a privilege to lead the Premier League through the last two seasons – when the spirit of English football has been more important than ever."
"Now, I have decided the time is right for me to stand aside to allow new leadership to steer the League through its next exciting phase."
