Moore, 49, departs Hillsborough after just over two years despite guiding the Owls to promotion to the Sky Bet Championship last month.
Wednesday beat Barnsley 1-0 after extra-time in the League One play-off final after they had overcome an unprecedented 4-0 first-leg deficit in their semi-final against Peterborough.
They also ended the regular season with 96 points - the highest third-tier total to have ever been accrued and not clinched automatic promotion.
Owls chairman Dejphon Chansiri told the club’s official website: “Both parties believe that now is the right time we go our separate ways.
“The journey of Sheffield Wednesday with Darren has been in many ways unique and always as a team. In the football industry, journeys come to an end and now is that time, which we both agree.”
Former West Brom and Doncaster boss Moore added: “I would like to take this time to acknowledge the chairman, Mr Chansiri, for giving me the opportunity to manage this great football club in Sheffield Wednesday, it’s been a journey in every sense.
“Both the chairman and myself have been determined to get this club back into the Championship.
“I’m delighted this has been achieved, and I hope the football club continues to develop and will soon fulfil the dream of mine, which was to take them back to the Premier League where they belong.”
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