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"The environment would be entirely suitable for them to come out," Scudamore told BBC Newsnight.
There have been no openly gay male footballers in England since former Norwich striker Justin Fashanu in 1990.
The Daily Mirror has reported that two top-flight players are set to come out with support from their clubs.
"It would be welcomed and I think there would be a tolerance to it. I think the time would be right to do that," Scudamore added.
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Former England women's captain Casey Stoney was the first active footballer to come out in England since Fashanu in February 2014.
Former Aston Villa midfielder Thomas Hitzlsperger publicly revealed his homosexuality in 2014, after his retirement, and Scudamore is "absolutely sure" there are gay players in England's top flight.
"It would be very strange if there wasn't," the Premier League chief executive said.
In other sports, high-profile athletes have openly spoken about their sexuality, with Olympic diver Tom Daley revealing in December 2013 he was in a relationship with a man.
British race walker Tom Bosworth became the first Team GB athlete to come out as gay, while former British and Irish Lions captain Gareth Thomas, who played rugby for Wales in both codes, and rugby league player Keegan Hirst have also come out.
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Examples in football are less common. In 1990, former England Under-21 international Fashanu was the first professional footballer in Britain to come out as gay. He retired from football in 1997 and took his own life a year later, aged 37.
Swedish footballer Anton Hysen, son of former Liverpool defender Glenn Hysen, announced his sexuality in an interview with a Swedish football magazine in 2011.
In February 2013, former United States and Leeds United winger Robbie Rogers said he was gay in a post on his website.
Arsenal manager Arsene Wenger said last year a gay Premier League footballer may never be able to reveal his sexuality during his playing career because of the intense scrutiny he would be under.
And retired basketball star John Amaechi, the first NBA player to come out, has called football "toxic" for gay people and minorities.
Gay footballers would be treated with respect if they choose to publicly reveal their sexuality, says Premier League boss Richard Scudamore.