Guillaume's education includes Lycée Robert-Schumann in Luxembourg;[3] Swiss boarding schools the Institut Le Rosey and the Collège Alpin International Beau Soleil where he finished the French baccalaureate in 2001;[3] and Royal Military Academy Sandhurst, Camberley, England.

[5] The Hereditary Grand Duke completed internships at the Belgian Chemical Union in 2003, at the Deutsche Bank in London in 2004, and at the Spanish branch of ArcelorMittal in 2005.

[6] In 1999, he participated in a charitable mission in Aguascalientes to provide the educational and social assistance to young people in one of the most deprived areas in Mexico.

After having chaired the Kräizbierg Foundation, which works for people with disabilities, for more than 10 years (2000–2011), the Hereditary Grand Duke accepted the title of honorary president in March 2011.

[6] Since 18 January 2016, the Hereditary Grand Duke has been a member of the board of directors of Europäische Stiftung Kaiserdom zu Speyer Foundation.

[6] On 8 October 2024, as had been announced by Grand Duke Henri on his Official Birthday that year, Prince Guillaume was appointed as lieutenant representative (regent).

[7] Under this capacity, he assumed a number of his father's constitutional powers,[8] such as the swearing in of ambassadors and the signing of Grand Ducal Decrees.

On 26 April 2012, the court announced the engagement of the Hereditary Grand Duke to the Belgian Countess Stéphanie de Lannoy.