Vicky Featherstone, who has overseen successes such as Black Watch during her eight-year stint since the NTS's creation in 2004, is to become artistic director of the Royal Court in London from April next year.
As Scotland's arts community absorbed the news of the decision, Ms Featherstone, who leaves the NTS at the end of the year, said she had taken the decision with "a complete mixture of real sadness and joy".
The NTS board will now begin the process of recruiting her successor.
Besides Black Watch, which is still touring internationally, Ms Featherstone's other successes include the Strange Undoing of Prudencia Hart, Beautiful Burnout, The Wolves in the Walls, Appointment With The Wicker Man, Enquirer and The Wheel.
She will be the first female head of the Royal Court after succeeding Dominic Cooke.
Ms Featherstone said: "It is a life-changing experience to be the person to set up a new national theatre.
"It is an honour beyond words to have played a part in something which is so great.
"It is a privilege to have seen the astonishing team at the National Theatre of Scotland grow into something fearless and dynamic. All I hope is that what we have created is something with enough importance, with enough care and with enough passion to last the future."
Ms Featherstone has been credited for sticking to her vision of the company as a hub for new writing and co-productions as well as a determination not to be financially hamstrung with a single venue base.
The NTS has also showcased writers such as David Greig, David Harrower, Zinnie Harris and Douglas Maxwell. Hollywood actor Alan Cumming is currently in rehearsals for Macbeth.
Richard Findlay, chairman of the NTS, said: "Vicky has done a fantastic job during her time here with many a great success built around a strong team.
"She will be sorely missed, not just by us, but by the entire Scottish theatre community."