In the 1997 election he was elected to Parliament for Enfield Southgate, the constituency in which he had been born and raised, with a majority of 1,433.

Twigg was the first man to be openly gay at the time of his election to the House of Commons when he was elected at the 1997 general election: it was a close contest for this record, as just 21 minutes later Ben Bradshaw, also openly gay, was elected for Exeter.

In the 2001 election Twigg held the seat with an increased majority of 5,546 over Conservative John Flack. Following the 2001 election, Twigg was appointed Parliamentary Secretary to the Leader of the House of Commons, Robin Cook, and in 2002 became a junior minister in the Department for Education and Skills. In 2004, in the government changes following the resignation of David Blunkett, he was promoted to Minister of State for school standards.

Whilst an MP he served as chairman of two All Party Parliamentary Groups - on epilepsy and on youth issues. He is a former chairman of Labour Friends of Israel.

In the 2005 election, Twigg lost his seat to the Conservative Party candidate, David Burrowes, by a margin of 1,747 votes (a swing of 8.7%).

He was selected as the Labour Co-operative candidate for the Liverpool West Derby constituency at the 2010 general election. He was elected with a majority of 18,467, garnering 64.1% of the vote.

On 7 October 2011 he was appointed to the post of Shadow Secretary of State for Education, following the Shadow Cabinet reshuffle.