Following a successful operation for breast cancer earlier this year, Dr St John-Brooks, 53, said it was with sadness that she had decided to relinquish the helm in order to make a full recovery.
She said: "Although I returned to work in July, I haven't been able to rediscover the high energy levels which are required to run The TES, so I have decided to take a career break for six months.
"I much regret saying goodbye to the paper and my wonderful colleagues, but I am sure I have made the right decision. I must say, though, that I never expected to be resigning my editorship on the same day that Chris Woodhead announced he was switching to journalism."
Dr St John-Brooks, a mother of two, has overseen a substantial and successful expansion of the newspaper. Since she took up her post, The TES has launched Primary and Friday magazines, Online (the TES computer supplement), the TES Curriculum Specials, and, most recently, College Manager. irculation of the main paper is almost 135,000.
Her editorship began on May 1, 1997 - the day new Labour swept to power - when she pledged to turn the paper into the key forum for debate on educational issues.
It was during her final year as an English literature student at Trinity College, Dublin, that she became fascinated by education, in particular by "how a society decides which aspects of the culture it wants to pass on to the younger generation, and how that can best be achieved".
Her career has included stints as education correspondent for New Society, as education editor of the Sunday Times, and three years in Paris researching education for the Organisation for Economic Cooperation and Development.
Sir Edward Pickering, chairman of The TES's parent company TSL Education Limited, said: "Caroline has both modernised the title and broadened its appeal to teachers and indeed everyone who is interested in education.
"I accept her resignation with great sadness but I fully understand the reasons for her early departure."
Bob Doe, currently deputy editor, will become acting editor.