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. In 1999, she appeared in the first four episodes of the first series of prison drama Bad Girls, portraying teenage mother Rachel Hicks who suffered endless bullying and committed suicide.

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 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.

Froggatt portrayed Kate, a peasant, in the third season of the BBC TV series Robin Hood. She played Hannah, in Spooks: Code 9, and features in the BBC Radio adaptation of Solaris as Rheya. In May 2009, she played Kelly on BBC drama Moving On.

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 15 April 2010, Froggatt appeared opposite Lee Ingleby in the BBC Radio Four play The Disappearance by Peter Walley. In her film début, In Our Name, Froggatt played Suzy, a soldier suffering from post-traumatic stress disorder. She garnered critical acclaim for her performance and won Best Newcomer at the British Independent Film Awards.

Starting in 2010, Froggatt appeared in Downton Abbey as Anna, lady’s maid to Lady Mary Crawley, for which she received an Emmy nomination in both 2012 and 2014. On 11 January 2015 she was awarded the Golden Globe for Best Supporting Actress in a Series, Mini-Series or TV Movie for the role.

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. In February 2020, she confirmed they had separated.

Along with Downton Abbey in 2013, Froggatt also had roles in the comedy drama based on Irvine Welsh’s novel, Filth, in the thriller uwantme2killhim? and the indie directed by Uberto Pasolini, Still Life.

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. In 2016 she starred in a two part ITV miniseries Dark Angel, based on the true story of Victorian poisoner Mary Ann Cotton. Also in 2016 she co-starred in a dramatisation of a real-life story “Starfish” as Nic, wife of Tom Ray who contracted sepsis and left with life-changing disabilities.

In 2017, Froggatt appeared in the lead role of schoolteacher Laura Neilson in the six-part thriller miniseries Liar on ITV. Her character awakens convinced that she was raped by respected surgeon Andrew Earlham (Ioan Gruffudd), who is also 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 aired in the U.S. on SundanceTV.

Froggatt made her stage debut on 25 February 2019 as Frances Thorpe in the thriller Alys, Always at the Bridge Theatre in London. The play was directed by Nicholas Hytner and written by Lucinda Coxon and based on the book by Harriet Lane.