A political science graduate, Monica Frassoni was elected Secretary General of the European Federalist Youth in 1987 and moved to Brussels. From 1990 to June 1999 she worked at the Green Group in the European Parliament as head of constitutional affairs.

In 1999 she was elected MEP on the lists of the Belgian Francophone Greens Ecolo, the first Italian elected abroad. In 2004, she was reappointed to the European Parliament for the Italian Greens. From 2002 to 2009, she was Co-Chair of the Green Group with Daniel Cohn-Bendit. She was Co-Chair of the European Green Party from October 2009 to November 2019. Since 2020, she has chaired the City Council of Ixelles, a municipality in the Brussels Region.

In 2011 she co-founded and has since then chaired the European Alliance for Energy Saving (EUASE), an organisation composed of leading companies specialising in energy efficiency technology and civil society organisations committed to the same issue. Since 2013 she has been president of the European Centre for Electoral Support, (ECES) an organisation specialising in electoral assistance projects in developing countries.

She joined Europe Jacques Delors in 2024 as an associate researcher focusing on green diplomacy and agri-food policy.