She studied economics and political science at the University of Amsterdam, graduating summa cum laude in 1993. During her study she also finished internships at the United Nations, Shell, ABN AMRO and the Ministry of Foreign Affairs. In addition to Dutch, she speaks fluent English,Spanish and French and also learned Slavic languages during her work in the Balkans. During her university years, she showed special interest in human rights situations around the world, and later specialized in Balkan diplomacy and international relations. In 1995 she was present at the peace conference in Dayton, Ohio.
She has been part of numerous international organizations that promote peace. She was a co-founder of War Child Netherlands in 1995, and served on its board until 1999. She was appointed director of EU affairs of the Open Society Institute in Brussels in 1997, and she was involved in the London branch as International Advocacy Director. She is one of the founding members of the European thinktank European Council on Foreign Relations. She is also a member of the Interpeace Governing Council.
From July 2008 till May 2012 she was the first Chief Executive Officer of the Global Elders, a group of eminent individuals convened by Nelson Mandela to use their wisdom, independent leadership and experience to tackle some of the world's toughest problems. She oversaw the day-to-day operations for the Elders.
She married Prince Friso of The Netherlands in 2004, but the union was not met without controversy. The marriage took place with the necessary approval of Parliament, resulting in Prince Friso (who was second at the time after his elder brother)'s loss of succession to the Dutch throne. The reason was that she had given "incomplete and incorrect information" about the duration and extent of her contacts with known drug lord, Klaas Bruinsma, and that because of this, the government had decided not to seek permission for the marriage from parliament. In a letter to the Prime Minister dated 9 October, Prince Friso stated that the couple had given some incomplete information, but had not given any incorrect information nor did they lie. The couple admitted that the sailing friendship with Bruinsma was indeed closer than had been mentioned, but denied a love or sexual relationship.
Princess Mabel and Prince Friso have two daughters, neither of which are in line for the Dutch throne. The elder, Emma Luana Ninette Sophie was born in London on 26 March 2005.She is called Luana, a Teutonic name meaning 'graceful warrior' (also 'gracious warrior' or 'female warrior'). The only information the couple released to the press after the birth of their daughter were three official photographs. Luana was christened by Huub Oosterhuis on 18 December 2005, in The Hague.Their second child, a girl named Zaria (full name Joanna Zaria Nicoline Milou), was born in London on 18 June 2006.
Since her marriage, Mabel Wisse Smit may use the courtesy titles of Princess of Orange-Nassau, Countess of Orange-Nassau, Mrs. Van Amsberg. She was not legally created a princess, but received courtesy titles due to her marriage, since it is customary for wives of members of the royal family to take the titles of their husbands. It was decided that their children each would receive the titles of Count or Countess of Orange-Nassau and Jonkheer or Jonkvrouw van Amsberg.