The Championship club said in a statement on Wednesday that the 55-year-old, whose previous managerial stint at the Rams was between September 2013 and May 2015, had signed a contract to the end of the 2017/18 season.
Caretaker manager Chris Powell will stay on as assistant, along with other backroom staff.
Derby, currently 20th in the 24-team second tier, parted company with Nigel Pearson last weekend after the former Leicester City manager had been in the job for four months.
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Club president Sam Rush said McCLaren had helped transform Derby last time around and had always been a prime candidate as "the architect of our style of football".
McClaren, who was England manager for 16 months from 2006-07 and left Derby under a cloud after being constantly linked with the manager's job at Newcastle United, said he was looking forward to the task ahead.
"I regret how my time at Derby ended back in 2015 and I am very motivated to put things right for the club and our supporters," said the manager, who joined Newcastle after leaving Derby but was then sacked by them last March.
"My ultimate aspiration remains exactly what it was before, to take Derby County back to the Premier League."
(Reporting by Alan Baldwin,; Editing by Neville Dalton)
