Neil McArthur leaves the regulator at a time when the commission is consulting on a significant overhaul of betting laws, focusing in particular on online gambling and casinos, which have seen a surge in customers during Covid-19 restrictions.
The boss joined the commission in 2006 and was General Counsel before rising to the top job in 2018.
Mr McArthur said: “We have taken significant steps forward to make gambling fairer and safer and I know that I leave the organisation in a strong position to meet its future challenges.
“With a review of the Gambling Act under way, now feels the right time to step away and allow a new chief executive to lead the commission on the next stage in its journey.”
An interim boss will be appointed as chairman Bill Moyes prepares to stand down later this year, allowing the next chair to appoint a permanent chief executive.
Deputy chief executive Sarah Gardner and chief operating officer Sally Jones will jointly become acting chief executive until an interim is appointed.
Earlier this year, Mr McArthur unveiled plans to introduce a series of strict new measures to protect players.
Online slot machines have soared in popularity during the Covid-19 pandemic as lockdowns and the cancellation of sporting events have seen gamblers turning to the games in record numbers.
By the end of October, online slot machine operators must limit the speed of the games, stop using sounds and images suggesting a “win” when the user has lost, and end the use of auto-play settings.
Slots are worth £2.2 billion and the industry is growing at around £100 million a year, according to the regulator.
The commission said it has focused on online slots because of its features which increase the intensity of play and the corresponding risks to players.
Proposals are also being made on affordability checks on gamblers once certain loss thresholds are reached, following scandals in recent years that had seen some bookmakers targeting vulnerable players to keep betting.
However, a recent YouGov survey commissioned by the Betting and Gaming Council, which represents UK bookmakers, found 51% of 1,683 adults polled are opposed to limits set by politicians versus 27% who support them.
Critics said setting affordability limits could cut more than £60 million from the amount of money horseracing receives from the betting levy.
Michael Dugher, chief executive of the Betting and Gaming Council, said: “Such a move would potentially also have serious ramifications for horseracing in particular, which relies heavily on the money it receives from the betting levy.”