An ECB statement said the former Australia international, 50, had informed the board she would not be seeking a contract extension.
Keightley has been in the role since January 2020. But on her watch England -- one of the best resourced women's teams in world cricket -- surrendered the 50-over World Cup title they had won on home soil five years ago with a crushing 71-run defeat by Australia, now the dominant force in the women's game, in this year's final in Christchurch.
Australia also overwhelmed England 12-4 in the most recent multi-format Ashes series. Keightley took England to the semi-finals of the 2020 T20 World Cup.
But only last week the team suffered the disappointment of missing out on a podium finish in the inaugural women's Commonwealth Games T20 competition, with the hosts narrowly defeated by India in the semi-finals before a heavy loss to New Zealand in the bronze medal play-off at Edgbaston.