Member of the European Parliament, 2004–2020

In early 2004, McGuinness declared her intention to seek a nomination for the European Parliament election for Fine Gael. This followed speculation linking her to a similar move for the Progressive Democrats. At the selection convention in February 2004, she was selected to run alongside Avril Doyle. This proved controversial^{[citation needed]}, as it was widely expected that Fine Gael could win only one of the three seats in the East constituency. However, a stronger than expected performance from Fine Gael in the election saw both women being elected.^{[citation needed]}

During her time in parliament, McGuinness served on several European Parliament committees, including the Committee on Agriculture and Rural Development and the delegation for relations with Australia and New Zealand. She was a substitute member of the Committee on the Environment, Public Health and Food Safety, the Committee on Petitions and the delegation for relations with China.^{[citation needed]}

McGuiness was a Fine Gael candidate for the Louth constituency at the 2007 general election, but was not elected.^[5] She was re-elected on the first count at the 2009 European election, topping the poll with 25.7% of the first preference votes.^[5]

In April 2011, McGuinness announced that she wished to run for President of Ireland and would seek the Fine Gael party nomination for the 2011 presidential election.^[6] In July 2011, she was defeated for the nomination by Gay Mitchell.^[7]

At the 2014 European election, she was re-elected to the European Parliament for the new Midlands–North-West constituency.^{[citation needed]}

In July 2014, McGuinness was elected Vice-President of the European Parliament;^[8] she secured an absolute majority to go through in the first round of voting by secret ballot.^[9] Under the leadership of President Martin Schulz, she oversaw the parliament's information policy, press and citizens relations. In addition, she served as chairwoman of the Working Group on Information and Communication Policy and as co-chair of the Inter-Institutional Group on Communication.^[10]

In addition to her committee assignments and duties as vice-president, McGuinness was a member of the European Parliament Intergroup on the Welfare and Conservation of Animals^[11] and the European Parliament Intergroup on Children's Rights.^[12] Alongside Karin Kadenbach, she also co-chaired the MEP Heart Group, a group of parliamentarians who have an interest in promoting measures that will help reduce the burden of cardiovascular diseases (CVD).^[13] In November 2016, One Voice For Languages^[14] welcomed McGuinness as their patron.^[15]

Also in November 2016, McGuinness officially announced her candidacy for the office of President of the European Parliament.^[16] Instead, Italian MEP and former European Commissioner Antonio Tajani was elected as the EPP group's nominee to replace incumbent president Martin Schulz; McGuinness received the second highest number of votes.^[17] Ahead of the 2019 European elections, she announced to run again for the post and was re-elected, exceeding the quota on the first count.^[18][19]

Following the 2019 elections, McGuiness was part of a cross-party working group in charge of drafting the European Parliament's four-year work program on digitization.^[20]

European Commissioner, 2020–present

McGuinness was one of two people, along with Andrew McDowell, who the Irish government nominated on 4 September 2020 for one position on the European Commission to replace Phil Hogan.^[21] On 8 September 2020, McGuinness was proposed by European Commission president Ursula von der Leyen as the new Commissioner for Financial Stability, Financial Services and Capital Markets Union.^[22] On 7 October 2020, she was confirmed to the post by a vote of 583–75 with 37 abstentions.^[23]

In November 2023, McGuinness announced she would not contest the 2024 European Parliament elections.^[24]