Avanti West Coast’s Pendolino train, named Royal Scot, set off from London Euston at 10.36am.
The firm said it is embarking on the record bid to highlight “the ease of travelling between the home nations”.
It is collaborating with Government-owned Network Rail which manages rail infrastructure, to plot the train’s path around passenger and freight services on the West Coast Main Line.
The existing record for the quickest train journey between the two cities is three hours, 52 minutes and 40 seconds.
That was set by British Rail in December 1984 using a prototype Advanced Passenger Train.
The quickest modern regular services on the route take around four-and-a-half hours.
The attempt at setting a new record is being made by a nine-carriage Pendolino train.
Royal Scot is running at 125mph – the maximum permitted speed on Britain’s mainline railway – for as much of the 401-mile (645km) route as possible.
Transport Secretary Grant Shapps said: “After almost 40 years it’s time for this record to be broken, and I wish everyone the best of luck as they attempt this impressive feat.
“Our rail network binds our Union together, and today’s attempt underlines why our clean, green railways is a great way to see the UK.”
Network Rail chairman Sir Peter Hendy said the event is a “brilliant collaboration across the railway industry”.
He added: “It shows how the clean, green railway of today can cement economic growth, jobs, housing and social cohesion through better connectivity across the United Kingdom.”
Sir Peter has been asked by Prime Minister Boris Johnson to examine how UK transport links can be improved, and will publish his final report this summer.
Steve Montgomery, managing director of Avanti West Coast’s parent company, First Rail said the record attempt “shows how effectively rail can deliver cross-border connectivity”.
He added that trains have an “essential role” in connecting major cities, driving economic growth and combating climate change.
The Railway Performance Society is the official timekeeper for the record attempt.
The train is carrying rail industry VIPs and subscribers to The Railway Magazine who made a charitable donation.
The money raised will go towards Avanti West Coast’s charity partner, Action for Children, and the Railway Benefit Fund, which supports people involved in the railway and their families.
