The girls, two of them 15 and one 16, have not been seen since Tuesday, when, police say, they took a flight to Istanbul.
One has been named as Shamima Begum, 15, who may be traveling under the name of 17-year-old Aklima Begum, and a second as Kadiza Sultana, 16. The third girl has not been named at the request of her family, police said.
Pictures released by police show the three girls walking together through London Gatwick Airport, carrying travel bags. They are said to be close friends who went to the same east London school.
Richard Walton, of Counter Terrorism Command, said: "We are extremely concerned for the safety of these young girls and would urge anyone with information to come forward and speak to police. Our priority is the safe return of these girls to their families.
"We are reaching out to the girls using the Turkish media and social media in the hope that Shamima, Kadiza and their friend hear our messages, hear our concerns for their safety and have the courage to return now, back to their families who are so worried about them."
UK police are concerned about the number of girls and young women trying to head to areas of Syria controlled by ISIS
, Walton said.
"It is an extremely dangerous place and we have seen reports of what life is like for them and how restricted their lives become," he said.
Besides being forced to lead a very limited life in Syria
, he said, they often are denied the choice of returning home, leaving few options for their devastated families.
However, if the three missing girls can be found while still in Turkey, there's a good chance they could still be brought home safely, he said.
A police statement urged anyone who thinks a family member might be planning to go to Syria to get in touch.
"This is not about criminalising people it is about preventing tragedies by offering support to the young and vulnerable," it added.
If the girls are headed to Syria, they would not be the first to attempt the journey.
In October, three teenage girls from Colorado were intercepted at Frankfurt Airport in Germany as they were trying to make their way to Syria to join ISIS. Their parents tipped off the FBI when they went missing.
Another Colorado resident, 19-year-old Shannon Maureen Conley
, was arrested at Denver International Airport before she departed on her journey to join an ISIS camp near the Turkish-Syrian border. She planned to marry a member of ISIS whom she had met online.
She was given a four-year prison sentence
last month after admitting wanting to become an ISIS bride and participate in its jihad in the Mideast.