Scudamore, 58, was appointed in 1999 and has been at the helm of the organisation for nearly 20 years, overseeing its growth into the world's most lucrative league and global money machine.
"I speak for all the clubs when I say we are very sorry that Richard will be leaving, but we could not have asked for anything more from him," Chelsea chairman Bruce Buck said in a Premier League statement.
"Whilst probably best known for the outstanding growth he has delivered, most importantly he commands the respect of everyone in football for the dignified and positive way he has managed the complexities of keeping the league together and moving us forward."
Buck said the board and audit committee expected to appoint Scudamore's successor "in good time" to ensure a seamless transition.
"The Premier League certainly will go on from strength to strength," he added. "When he eventually leaves later in the year it will be with our sincerest thanks and gratitude for a job well done."
The combined revenues of Premier League clubs increased by nearly 1 billion pounds ($1.4 billion) to a record 4.5 billion pounds in the 2016-17 season, according to data from Deloitte published in April.
Profitability is expected to continue despite a decline in domestic broadcasting revenue.
"It’s an absolute privilege to have been allowed to enjoy this role for so long, it is too much fun to be called a job," Scudamore said.
"The Premier League is in great shape and the future is bright, of course there are still many things to improve and constant challenges but that is what makes it so exhilarating," he added.
"The clubs put on the greatest show; fans, such an essential part of that show, love it both here and around the world. Because it so compelling, the League’s success will continue under new and re-invigorated leadership."
(Reporting by Alan Baldwin, editing by Ed Osmond)
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