Caroline, 14, was found partially submerged in the River Leven, near Place of Bonhill, Renton, at about 4.10pm on Sunday August 25 1996.
Police said they confirmed officers had arrested and charged the trio in connection with the death.
Donna Brand, 42, Andrew Kelly, 42, and Robert O’Brien, 43, appeared at Dumbarton Sheriff Court on Thursday charged with murder.
All three, whose general addresses were given as Dumbarton, made no plea and were remanded in custody.
Detective Chief Inspector Stuart Grainger, of the Major Investigations Teams, who is the senior investigating officer on the case, said: “I would like to thank the members of the public who have assisted with our investigation and those who have come forward with important information surrounding Caroline’s death.”
The long-running case has featured in a string of television documentaries and appeals and on BBC’s Crimewatch UK programme.
Caroline, from Bonhill, was a pupil at Our Lady and St Patrick's High School in Dumbarton at the time of her death.
She was last seen alive at at about 12.15am on August 25 walking down Dillichip Loan towards Dillichip Bridge, and then onto a towpath.
Her body was found at about 4.10pm later that day, about a mile from her home.
The arrests and charges came five years after the cold case was reviewed and an by Crimestoppers on the 21st anniversary of her death.
Caroline's mother Margaret McKeich previously said: "I am just waiting for that knock on the door telling me there has been a breakthrough.”