In 1996, Froggatt made her TV debut in the long-running ITV drama The Bill, and shortly afterwards landed the role of teenage mother Zoe Tattersall in Coronation Street. She left the programme in 1998 when her character was written out.

Froggatt's early TV appearances include Coronation Street (1997–98), Bad Girls (1999), Dinnerladies (1999) and A Touch of Frost (2003). She went on to star in the television films, Danielle Cable: Eye Witness (2003), See No Evil: The Moors Murders (2006) and Murder in the Outback (2007), beforewinning the British Independent Film Award for Most Promising Newcomer for her leading role in the 2010 film In Our Name. She played Mary Ann Cotton in the 2016 ITV miniseries Dark Angel.

In 2003, Froggatt played the leading role in the controversial one-off drama, Danielle Cable: Eyewitness, based on the true story of a teenage girl who witnessed the murder of her boyfriend in a reputed road rage attack. Whilst researching the role, she met Cable who later contacted her to commend her on her portrayal. The film earned a BAFTA TV Award nomination for Best Single Drama.

Froggatt played the role of Angelique Mahy in the ITV mini-series "Island at War", that tells the story of the German occupation of the Channel Islands. It aired on 11 July 2004. In the same year she played Myra in the BBC Radio 4 drama My Turn to Make the Tea by Monica Dickens.

Froggatt starred as a main character in the drama Missing, made by SMG Productions in 2006 alongside Gregor Fisher. However, the two-part thriller was not broadcast on STV until November 2008 because ITV had changed its format to 60-minute time slots and Missing was two 90-minute time slots.

Also in 2006, Froggatt played the sister of Myra Hindley in the ITV drama, See No Evil: The Moors Murders, and later appeared in another controversial role as the title character in Joanne Lees: Murder in the Outback, which first aired on Channel Ten in Australia on 18 March 2007, and was screened in Britain on ITV on 8 April 2007. The role involved the depiction of a real-life kidnap, in which Froggatt had to perform scenes tied up with tape around her mouth as a gag. She said she got a feeling of "helplessness" while filming the scenes. She also appeared on the London stage in the adaptation of All About My Mother in the part of Sister Rosa, which ran from July to November 2007 at the Old Vic Theatre.

On 25 September 2009, Froggatt played the title role in the BBC Radio Four play I am Emma Humphreys. On 3 October of that year, Froggatt played Princess Yvonne in the BBC Radio Four Saturday play The Von Trapps and Me.

On 25 December 2010, Froggatt appeared in the Royle Family Christmas special 'Joe's Crackers' as Saskia, the girlfriend of Antony Royle. Despite having been mentioned by name in earlier episodes, this was the first time that Saskia had appeared in person. Froggatt starred in John Donnelly's play The Knowledge at the Bush Theatre, West London from 12 January to 19 February 2011.

Froggatt married long-time boyfriend James Cannon in a private ceremony in October 2012. The couple live in Buckinghamshire, United Kingdom.

In 2013 Froggatt became an ambassador for global children's charity Plan UK's "Because I Am a Girl" campaign.

In 2015, she played Wendy in the new Bob the Builder series voicing her in both the UK and US versions.

On 11 September 2017, Froggatt débuted in her lead role, schoolteacher Laura Neilson, on the new six-part thriller miniseries, Liar, on ITV. She awakens convinced that she was raped by respected surgeon Dr Andrew Earlham (Ioan Gruffudd)--who also happens to be the father of one of her students--even though she can't remember the incident, nor does forensic evidence bear out her version of events. The series began airing in the U.S. on SundanceTV on 25 September 2017.