Venu Dhupa, the director of creative development at the body, last night announced her resignation, only two weeks after chief executive, Andrew Dixon, also quit.
Ms Dhupa, regarded as one of the key figures at the body which has endured a disastrous and controversial year, will leave next February with a £17,500 payoff – three months of her £70,000 salary.
Ms Dhupa was a controversial appointment to the quango – which distributes £80 million a year in Government and Lottery funds – following her departure from the British Council.
When she was director of arts at the British Council, the UK's cultural body, a letter protesting against a radical art-form funding shake-up was signed by luminaries such as Damien Hirst, Lucian Freud and David Hockney, and she left the British Council shortly after, in 2008.
Similarly, in October this year, a damning letter – signed by more than 400 artists and cultural workers – called for radical change at Creative Scotland, leading eventually to the departure of Mr Dixon.
Ms Dhupa was regarded as a key colleague of Mr Dixon and it was she who briefed the press on the controversial removal of Flexible Funding to more than 40 arts organisations earlier this year.
That decision has essentially now been reversed by the Creative Scotland board, and an internal report by one board member, Ruth Wishart, last week severely criticised the internal management of the body.
Ms Dhupa's departure leaves Iain Munro, creative director, as the de facto leader of the body.
Sir Sandy Crombie, the chairman of Creative Scotland's board, said: "I would like to thank Venu for her contribution to Creative Scotland.
"Venu has worked hard on behalf of the organisation and this is very much appreciated.
"Her work in the area of international engagement has moved us on significantly, with many new partnerships established for the benefit of Scotland."
Ms Dhupa said: "I have really enjoyed my time at Creative Scotland. We have facilitated some amazing art and creative work in the last two-and-a-half years, and not least made the biggest residency programme in Europe with several international partners.
"It's the talent that makes all this possible that should be the focus going forward."
She added: "Seeing social and cultural diversity as an opportunity and having the courage to look outwards will be an important element for Scotland's success.
"I have travelled the length and breadth of the country and met some wonderful people who are the creative heartbeat of Scotland and I look forward to celebrating their achievements in future, albeit from a different perspective."
Following a period of hand-over, Ms Dhupa will leave Creative Scotland at the end of February 2013.
Before taking up her roles at the British Council and Creative Scotland, Ms Dhupa had been the chief executive of Nottingham Playhouse and head of arts at the National Endowment for Science, Technology and the Arts.