UN official Jacqueline Badcock said the fatwa, or religious edict, applied to females between the ages of 11 and 46.
She said the unprecedented decree issued by the Islamists in control of the city was of grave concern.
Iraq is facing a radical Isis-led Sunni insurgency, with cities in the north-west under militant control.
The ritual cutting of girls' genitals is practised by some African, Middle Eastern and Asian communities in the belief it prepares them for adulthood or marriage.
'Four million'The UN General Assembly approved a resolution in December 2012 calling for all member states to ban the practice.
The Isis edict could affect nearly four million women and girls in and around the northern Iraqi city of Mosul, the UN warns.
Ms Badcock, the UN's resident and humanitarian coordinator in Iraq, said the practice "is something very new for Iraq... and does need to be addressed".
She was talking to reporters via video link from the Kurdish provincial capital of Irbil.
"This is not the will of Iraqi people, or the women of Iraq in these vulnerable areas covered by the terrorists," she added.
Isis militants seized Mosul, Iraq's second largest city, in June, and have since taken over areas of the north-west and closed in on cities near Baghdad.
The order came as Isis asserts its power in northern Iraq and expands in Syria, imposing radical Islamic practices, says the BBC's Lina Sinjab.
Isis forced Christians in Mosul out of the city earlier this week and daubed their houses with the Arabic letter N to mark them out as Christians, apparently confiscating their properties, our correspondent adds.
Ms Badcock said only 20 families from the ancient Christian minority now remain in Mosul, which Isis has taken as the capital of its Islamic state.
Thousands have fled into Kurdish-controlled territory in the north.
Some of the Christians who remained have converted to Islam, while others have opted to stay and pay the "jiyza", the tax imposed by Isis on non-Muslims, the UN official added.
Isis announced last month that it was creating an Islamic caliphate covering the land it holds in Iraq and Syria.
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