Mellor joined the children's charity in January last year from The Sunday Times, which he had joined after the closure of News International stablemate the News of the World.
He has also worked for the Daily Mirror and Sunday Telegraph.
After less than 18 months at Barnardo's, he left the charity last week and takes up the role of news editor at the Mail on Sunday on 5 June. He will report to MoS head of news David Dillon.
Mellor said: "I'm delighted to be heading to The Mail on Sunday and back into national newspapers where I've spent most of my career.
"Becoming news editor of such an influential and agenda-setting newspaper is a huge privilege, but I'm sorry to leave Barnardo's where I made many friends and gained a valuable insight into both the opportunities and challenges of PR."
Nick Gammage, who has been Barnardo’s interim director for comms since the Autumn, said: "James is a terrific newspaper man through and through. I am grateful for the way he brought a sharp focus on the killer angle, on people and on keeping it simple to Barnardo’s news and feature output.
"The news desk is his natural home and he will be a great asset for the Mail on Sunday news operation." Mellor's father Phil was also a career newspaper man, most notably on the Mirror.