The Liberal member for Vaucluse, who was the first woman to serve as the state's attorney general, said she had "given everything" to her political calling but had decided it was the right time to retire.
"I have had almost 12 amazing years representing my local area as their MP, serving as a minister in the Liberal coalition government across four portfolios and as parliamentary secretary to two premiers," Ms Upton said in a statement on Wednesday.
"Most proudly, I served as both the first female attorney general and the first female Liberal sports minister in NSW.
"I have given everything I have to this calling - my heart, energy and passion - and I have loved every minute of it."
During her tenure as attorney general, Ms Upton introduced a pilot scheme to provide specialist support to child victims of sexual assault and allow them to pre-record court evidence without a jury present.
Ms Upton also held ministries in various other portfolios, including local government, the environment and community services.
She said it was time for her to "do something new" and allow another MP to take her place, adding: "I know in my heart that this is the right time to retire."
NSW Premier Dominic Perrottet thanked Ms Upton for her time in the parliament, adding that she was "a bit emotional" when she called him with the news on Tuesday night.
"I think New South Wales is much better off for her decade of service to our great state, and also the people of Vaucluse," he said.
Mr Perrottet said a preselection process for the seat would take place within the NSW Liberal Party ahead of Ms Upton's exit from parliament at the March state election.
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