Greater Manchester Police said: 'The girls flew from Manchester International Airport to Istanbul.
'Since their departure the girls have been in contact with their family.
'We are attempting to confirm their current location and secure the well-being of both girls.'
The family, of Somalian origin, is believed to have moved to Britain 10 years ago.
According to The Sun on Sunday, the strictly religious schoolgirls have told their family they are not coming home.
'The family have been trying to persuade their daughters to come home but so far they have said they are happy to stay,' a source told the paper.
Police are now probing where the girls got the money to fly to the Middle East.
The sixth formers' disappearance comes as the Home Office battles to counter calls from ISIS to British teenagers to join them.
Extremists have used Twitter and YouTube to reach out to young Muslims across the world.
And on Friday, ISIS leader Abu Bakr al-Baghdadi emerged from relative recluse to issue a plea for all Muslims to 'obey' him in his quest for world domination.
A video of Baghdadi's sermon at the Great Mosque in Mosul, Iraq's second largest city, was released on the internet yesterday and went viral instantly on jihadist forums and websites.
Speaking from the pulpit of the mosque, Baghdadi, 42, urged the world's Muslims to flock to the new Islamic caliphate. He praised the victory of his 14,000 fighters spread across Iraq and Syria.
This month, a video emerged of three British fighters gushing about their life in Iraq.
Among them was aspiring jihadi Aseel Muthana, who told the BBC he was fighting in Syria and had no intention of returning to the UK.
His brother Nasser appeared with two other British men - 20-year-old Reyaad Khan, from Cardiff, and Abdul Raqib Amin, who grew up in Aberdeen.
n April, the Metropolitan Police issued a plea for people to come forward with information about their family members if they were concerned about them joining terrorist training camps in Syria.
And a British Jihadi who claims he is fighting alongside militants in Syria has said he will return to the UK when he sees 'the black flag of Islam' hanging over Buckingham Palace.
The man, who called himself Abu Osama, said he had been taking part in military training, making bombs and fighting with the extremist Al-Nusra Front, which is linked to al Qaida, for the past year.
Osuma, whose accent suggested he comes from the north of England, claimed to have been fighting for the establishment of a caliphate - which he referred to by the Arabic term Khilafah - across the Islamic world.
He told BBC 5 Live's Nicky Campbell: 'There is nothing in Britain - it is just pure evil.
'If and when I come back to Britain it will be when this Khilafah - this Islamic state - comes to conquer Britain and I come to raise the black flag of Islam over Downing Street, over Buckingham Palace, over Tower Bridge and over Big Ben.'
- Daily Mail