In 1990, she became the president of the Young Entrepreneurs Group of Syracuse, Sicily.[6]
In 1994 she joined the Chamber of Deputies as member of the Forza Italia party.[6] She was reelected in 1996, 2001,[6] 2006, 2008.
In 2004, she was appointed as Minister for Equal Opportunities by Prime Minister Silvio Berlusconi.[6] She was reappointed in that capacity in 2006. Between 2008 and 2011, she was Minister for Environment, Land and Sea.
Stefania Prestigiacomo has expressed support for the construction of new nuclear plants in Italy, a country with very limited reserves of fossil fuel and that currently imports (nuclear) electricity from France due to insufficient domestic capacity. She also authorized the drilling of off-shore oil wells in the Adriatic Sea in the proximity of Tremiti Islands, a natural maritime park.
She is President of the Inter-ministerial Coordination Committee for the fight against Paedophilia (CICLOPE).[6] She is a Catholic.