Moira Anderson was 11 when she vanished on February 23, 1957, while on an errand for her grandmother in Coatbridge.
Officers suspect that convicted paedophile Alexander Gartshore, who died in 2006, was responsible for her death.
He was driving a bus boarded by Anderson during a snow storm on the day she went missing but was never charged.
Police, led by Detective Superintendent Pat Campbell, are now acting on new witness statements that link Gartshore to a section of the Monkland canal at Carnbroe, a housing estate between Airdrie and Coatbridge.
The waterway closed to traffic in 1952 and the section in question has changed little in the six decades since.
Det Supt Campbell said today that an operation, involving forensic experts from across the UK, would search the canal in the hope that Anderson’s remains could finally be found.
The initial four-day search includes the use of enhanced technology including ground penetrating radar to identify any anomalies at the base of the three-metre deep canal.
Magnetometry (identification of magnetic anomalies) and earth science techniques will be applied to determine if there is any evidence of the child’s remains at the bottom of the canal.
Anderson’s next-of-kin were made aware of the developments in recent weeks and are supporting the police search.
Det Supt Campbell added: “We have continued to investigate the disappearance of Moira over the years and new evidence has come to light that has brought our attention to the Monkland Canal in Carnbroe.
“We have engaged with a number of leading experts to assist us with this case and they have helped to identify this specific site. These people are experts in forensic soil analysis and the use of innovative search techniques and they will very much play a live part in the search of this site.
“At this stage, we are hopeful of finding any evidence that could help us resolve the investigation into Moira’s disappearance. This canal has been largely left undeveloped for many years and it is hoped the ground-penetration radar and sonar scanning can help to identify any anomalies within the silt layer at the base of the canal.
“This is a positive although extremely challenging step in the investigation due to the passage of time, however I remain optimistic about the forthcoming search.
“Ultimately we hope to identify a deposition site and to recover the remains of Moira, which would bring some form of closure to her family and the local community, who have endured years of uncertainty.”
Anderson left her grandmother’s house in Muiryhall Street, Coatbridge, at 4.10pm on Saturday, February 23, 1957, to buy margarine from the nearby Co-op.
She was reported missing to the police later that night and has not been since by her family.
Strathclyde Police and laterly Police Scotland have periodically investigated her disappearance.
The case was reviewed by an investigation team led by Dep Campbell in conjunction with the Cold Case Unit at the Crown Office and Procurator Fiscal Service (COPFS).
As a result of new evidence, COPFS concluded that Gartshore would have been indicted if he had still been alive for Moira’s abduction and homicide.
In January 2014, COPFS publicly stated that Gartshore would have been indicted for Moira’s murder as there is sufficient credible and reliable evidence.