Van Oranje is an advisor to several non-profits, including the Coalition for the International Criminal Court, the Malala Fund, Crisis Action and the Open Society Foundations.

In 1984, her mother remarried to Rabobank executive Peter Wisse Smit (15 October 1939 – 11 November 2000), whereupon Mabel and her younger sister, Nicoline (1970–2023), took their stepfather's surname.

After attending her secondary education at the Gemeentelijk Gymnasium Hilversum, she studied at the University of Amsterdam, where she graduated cum laude with a master's degree in economics and political science in 1993.

[citation needed] During her university years, she showed special interest in human rights situations around the world, and later specialised in Balkan diplomacy and international relations.

[7] From July 2008 until May 2012, she was the first Chief Executive Officer (CEO) of The 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.

[8] In May 2012, Mabel van Oranje resigned as CEO of The Elders following the February 2012 accident in which her husband, Prince Friso, was caught in an avalanche and remained hospitalised until his death on 12 August 2013.

In 2015, she was one of 35 signatories to an open letter addressed to Angela Merkel and Nkosazana Dlamini-Zuma, heads of the G7 in Germany and the African Union (AU) in South Africa, respectively, from the ONE Campaign.

As the G7 and AU prepared for the United Nations summit later that year, the letter called for them to put women and girls at the heart of international efforts to combat hunger and misery.

The couple has two daughters: As he had not asked the Dutch parliament for permission to marry, Friso ceased being a member of the royal house and forfeited his and his future children's succession rights.