Keightley will leave her position at the end of the summer.
The Australian was the team's first full-time female head coach.
She told theECB that she wouldn't be seeking a contract extension.
England made it to the semi-finals of the 2020 Women's T20 World Cup under her leadership.
Her last series will be in India.
Keightley was the first woman to score a century in an one-day international when she did it at Lord's.
She was the head coach of the Perth Scorchers in the Women's Big Bash League.
The recruitment process for her replacement will begin before the T20 World Cup.
The director of women's cricket said they were grateful for the commitment and passion Lisa had shown over the last two and a half years.
Competition for places has increased over the last year and the squad Lisa leaves is an exciting blend of youth and experience.
It's challenging to lead an international team. Lisa has been able to continue the development of the team despite what has been the toughest period we have faced off the field during a Pandemic.
"Lisa was always a fierce opponent when she represented Australia, and she's brought that same pride, passion and will to win into everything she's done with the England team," said the interim CEO.
I know the team will join me in wishing her well for her next challenge because they have enjoyed working with her.
Stephan Shemilt writes about cricket.
Even though England failed to win a medal at the Commonwealth Games, Keightley's departure was always going to happen.
She has not been able to visit her home in Australia due to the Pandemic Era.
She has been in charge of the team for a long time. In the World Cup final, Australia defeated England. England failed to reach the final of the T20 World Cup, despite the fact that they were done by the rain.
The job of Keightley's successor will be to close the gap between England and Australia.
It is likely to start with a tour of the Caribbean before Christmas, then the T20 World Cup in the spring, before the Aussies play in the summer.