In September 2020, after initially delaying its summer run, casting was revealed exclusively by the theatre website WhatsOnStage[8] for the upcoming revival of Rent at the Hope Mill Theatre in Manchester, which included Hesketh as a featured ensemble member. After opening to critically acclaimed reviews and a socially-distanced audience in November 2020,[9] the production had to close after five performances due to a newly imposed lockdown.[10] However, as a result, a series of online performances ran from 27 November to 20 December 2020 on the Hope Mill Theatres' website.[11] The show returned again to the Hope Mill Theatre in Summer 2021, with Hesketh also returning as a featured ensemble and alternate Angel for this iteration of the production.[12]
In March 2022, it was announced exclusively via WhatsOnStage that Iz would portray the role of Margot in the revival of Legally Blonde at Regent's Park Open Air Theatre.[13] This marked the first time Margot was played by a transnon-binary actor in a professional capacity. In an interview with media outlet PinkNews Hesketh said "I can't quite put into words how grateful I am to be taking this huge step in musical theatre history".[14] In response to the transphobic backlash, Iz said "You've made my determination to change this industry that little bit stronger today (...) If anyone feels like I'm not right for this part or that I won't be able to do this role as well as a cis female, PLEASE feel free to drop me a message and I'll be more than happy to buy you a ticket to watch the show so you can sit there for the duration and be proved wrong".[15] The highly praised production ran from May–July 2022, and included a performance at the annual West End LIVE event held in Trafalgar Square by the Society of London Theatre, Westminster City Council and the Mayor of London.[16][17]
At the beginning of 2022, casting was revealed for the European premiere at the Hope Mill Theatre in Manchester, of the jukebox musical Head Over Heels (based on the music of The Go-Go's) this included Iz as the principal character Pythio, an oracle to the fictional kingdom of Arcadia.[18] The production ran from 26 January to 4 March 2023.[19] In early May, WhatsOnStage exclusively revealed the casting of new Weimar-era Berlin musical Fury and Elysium at The Other Palace that included Hesketh portraying Anita Berber,[20] the production ran for a limited run of two weeks in June 2023.[21]
Hesketh also features on the live cast recording of Olivier-nominated autobiographical play My Son's a Queer (but What Can You Do?) and participated in the West End LIVE performance.[22]
In January 2024, it was announced via the official Hollyoaks social media channels and Hesketh's Instagram[23] that she would star as Kitty Draper in long-running British soap opera, Hollyoaks. In March of that same year, Hesketh announced her role as Valerian in the British historicaladventure television series Renegade Nell on Disney+.[5] She is the first person to portray a non-binary character to appear in a Disney live action series.
In mid-July 2024, Iz won the award for Best Newcomer at the RadioTimes.com Soap Awards 2024. When speaking to Radio Times, she revealed that winning the award felt "unreal" and went on to say receiving the accolade was "absolutely incredible, yeah I'm just buzzing".[24]