Hesmondhalgh is best known for playing Hayley Cropper in the ITV soap opera Coronation Street. Making her debut appearance on the show in 1998, she played the first transgender character in a British serial. She took time off from the soap between 2000 and 2001 to give birth to her first daughter. After nearly ten years on the show, Hesmondhalgh decided to take another break for a year in order to spend more time with her family. She left on 22 October 2007, but returned on 17 November 2008. On 24 December 2011, Hesmondhalgh appeared on ITV’s The Cube, winning £20,000 for her Accrington-based anti-poverty charity, Maundy Relief.

Her character Hayley was involved in high-profile storylines, including one concerning a gender transition, and a hostage storyline in the Underworld factory in which Hayley and Carla Connor (Alison King) were kidnapped, bound and gagged by Tony Gordon, who intended to murder them, although they escaped. On 11 January 2013, ITV announced that Hesmondhalgh would be leaving Coronation Street in January 2014 after 15 years in the show, and that her character Hayley was to leave in a controversial right-to-die storyline, following a battle with pancreatic cancer. She filmed her final scenes on 18 November 2013; they aired on 22 January 2014, the night she won a National Television Award for Best Performance in a Serial Drama, which she shared with her longtime co-star, David Neilson. She worked with pancreatic cancer charities to raise awareness of the disease, and was involved in a petition and attended a parliamentary debate on the subject in 2014.

On 1 May 2013, Hesmondhalgh appeared on ITV game show All Star Mr & Mrs with husband Ian, and won £20,000 for Maundy Relief.

From 19 to 29 September 2012, Hesmondhalgh appeared at the Royal Exchange Theatre in Manchester, portraying Sylvia Lancaster in Black Roses: The Killing of Sophie Lancaster opposite Rachel Austin. The play was based on the real-life story of Sylvia’s late daughter, Sophie Lancaster. Hesmondhalgh won a Manchester Theatre Award for Best Studio Performance in 2013.

On 23 January 2014, she returned to the Royal Exchange Theatre for her first role since leaving Coronation Street, in the Simon Stephens play Blindsided, which ran until 15 February. From 12 November to 20 December 2014, she appeared in God Bless The Child at the Royal Court Theatre in London, directed by Vicky Featherstone, playing Mrs Bradley, with Amanda Abbington.

From 22 January 2015, Hesmondhalgh played the role of Cleo Whitaker in the Channel 4 drama series Cucumber, written by Russell T Davies. She also appeared in the BBC Four film Black Roses: The Killing of Sophie Lancaster, a television film about the murder of Sophie Lancaster. Hesmondhalgh played the role of Sophie’s mother, Sylvia Lancaster, a role which she previously portrayed on stage. Hesmondhalgh is friends with Sylvia Lancaster and patron of the Sophie Lancaster Foundation. In 2015, Hesmondhalgh won a Royal Television Society Award for Best Female Actor in a Drama for her role as Sylvia.

In 2015, she appeared in an episode of the BBC drama Moving On, with Shane Richie and John Thomson, as well as the one episode of Inside No 9, written by Steve Pemberton and Reece Shearsmith.

In June 2015, Hesmondhalgh performed a script-in-hand scratch performance of her first one-woman play, These I Love, at Gulliver’s in Manchester.

She is a founder member of a Manchester-based grassroots theatre company creating work about social issues, Take Back, which she runs with Rebekah Harrison and Grant Archer, and to which she has contributed as a writer and actor. She is a member of The Gap collective, a new writing company in Manchester and performed their first gala performance at Halle St Peters in September 2015, in a piece by her husband Ian Kershaw.

Hesmondhalgh is a Labour Party member. In August 2015, she endorsed Jeremy Corbyn’s campaign in the Labour Party leadership election. She tweeted: “Proudly supporting Jeremy Corbyn in the Labour leadership contest.” She campaigned for Corbyn as party leader in the 2017 UK general election. In May 2017, speaking at Labour’s general election campaign launch in Manchester, she said: “I realised the Labour party and its core values would finally be in line with my own deeply held socialist beliefs about equality, justice and peace.”

In 2016, Hesmondhalgh joined the cast of acclaimed drama thriller Happy Valley for its second series on BBC One. She was offered the role by creator, writer and executive producer Sally Wainwright. Hesmondhalgh’s character Amanda Wadsworth, is a midwife and working mother from Yorkshire who has a fraught relationship with her husband, John (Kevin Doyle).

In January 2016, she played Vivian Bearing, an American Professor of Poetry dying of ovarian cancer, in Margaret Edson’s Wit at The Royal Exchange main stage, directed by Raz Shaw, for which she was nominated for a TMA and won a Manchester Theatre Award for Best Female Performance.

In 2017, Hesmondhalgh played the lead role of Trish in the third and final series of Broadchurch on ITV.

On 30 April 2017, Hesmondhalgh starred in a one-off performance at the Royal Court Theatre, of Lemn Sissay’s The Report, directed by John E. McGrath.

In 2018, she was announced as a guest star in the Doctor Who episode “Kerblam!”.

In February 2018, she starred as Renee in The Almighty Sometimes by Kendall Feaver. It was directed by Katy Rudd at the Royal Exchange.

In 2019, she played Amanda in the first episode of the final season of Channel 4’s Catastrophe with Rob Delaney and Sharon Horgan. In March 2019, it was announced that she would be appearing in a new six part ITV comedy drama, The Trouble with Maggie Cole, with Dawn French.

In February 2019, she performed the title role in Mother Courage and Her Children by Bertolt Brecht, adapted by Anna Jordan. It was directed by Amy Hodge at the Royal Exchange, Manchester.

In 2019, she set up the group 500 Acts of Kindness, a fundraising community where 500 members donate a pound a week to give to an individual, group, family or organisation in need.

In 2020, she played Heather, Joe’s teacher in the third series of The A Word