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.