Derham was born in Stockport to John and Margaret Derham, and grew up in Wilmslow. She was educated at Cheadle Hulme School and read Economics at Magdalene College, Cambridge graduating with a BA (Hons).

On 3 August 2010 Derham hit out on the "perceptions of young female newsreaders".

Derham began her broadcasting career at the BBC, starting as a researcher on Radio 4's Moneybox. In 1995 she won the Bradford & Bingley "Best Personal Finance Broadcaster Award" for her work as a presenter on Radio 5 Live's Moneycheck. She moved to BBC television in 1996 as a consumer affairs correspondent and was also a reporter on the long-running Film programme.

In 1998 she joined ITN as the Media and Arts Editor for ITV News and, at the age of 27, became the youngest newscaster on British national television since ITN's creation in 1955. In 2004, Derham became the main female presenter of the ITV News at 1:30, and a relief presenter of both the ITV News at 6:30 and the ITV News at Ten. She also co-presented the ITV London news programme London Tonight. Derham hosted her last programmes on ITV1 on 25 June 2010.

In April 2010, it was announced Derham was to join the BBC. Derham has been given an arts brief, including fronting the coverage of the Proms for BBC Two, BBC Four and Radio 3.

Derham hosted the Classical BRIT Awards ceremony four times from 2001 to 2004. In August 2008 she appeared in the BBC Two talent programme Maestro.

Derham is a presenter of Radio 3's Afternoon on 3 and Breakfast programmes, having previously presented the Hall of Fame Concert on Classic FM, and she presents the Traveller's Tree series on Radio 4. Derham also makes the occasional guest presenter appearance on Saturday Live.

Derham married restaurateur John Vincent in 1999 in Cheshire. They have two daughters, both born in Westminster, London: Natasha May (born 2000) and Eleanor Margaret (born 2005). The family live in Sussex. She plays the violin.