Following Michael Gunner's resignation from the role of Chief Minister on 10 May 2022, Fyles was elected as his replacement by the Labor caucus on 13 May 2022.

She resigned on 19 December 2023 amid conflict-of-interest allegations due to her holding undisclosed shares in fracking and mining companies whose projects were greenlit during her tenure.

Amidst a CLP landslide, she unexpectedly lost re-election at the 2024 election, narrowly being defeated by Greens candidate Kat McNamara.

[6] On 24 September 2023, Fyles was allegedly assaulted with a cream-covered pancake by a member of the public at the Sunday markets at Nightcliff.

[10][11] However, she later divested the shares, stating she wanted to 'end the distraction',[11] also claiming that she had declared any financial interests from the past decade.

[10] Despite her previous statements that she had declared all financial interests, in December 2023, it was revealed that she holds 754 undeclared shares in South32, a company that owns a manganese mine on Groote Eylandt.

Fyles faced further conflict of interest allegations and calls to resign, due to Fyles' decision earlier in 2023 to not investigate health impacts from the Groote Eylandt mine, with Leader of the Opposition Lia Finocchiaro calling her actions a 'profound betrayal of public trust'.

[5] The next day, Fyles' treasurer, Eva Lawler, was announced as her successor, with Attorney-General Chansey Paech replacing Nicole Manison as Deputy Chief Minister.