The 51-year-old had been negotiating a release from his contract following a rift with the board over his budget.
Hughes has been with the Highlanders since December 2013 and won the Scottish Cup last year, the club's first major honour.
"John will be remembered as a member of a great winning team," read a brief statement from Inverness CT.
Hughes had become increasingly frustrated at the loss of key squad members and spoke of his disappointment when an approach from Dundee United was blocked earlier this season.
Having previously managed at Falkirk, Hibernian, Hartlepool and Livingston, he replaced Terry Butcher at the Caledonian Stadium.
As well as lifting the Scottish Cup, Hughes steered Inverness to a third place finish in the Premiership last season, with this campaign opening with their first taste of European football.
In March 2014, Inverness reached the League Cup final, losing on penalties to Aberdeen.
The Inverness statement contained a message on behalf of Hughes, saying: "I will look back on my time in the Highlands with a genuine fondness and warm affection for the club, the area and the community.
"The welcome I received from the fans and the response I got from the players throughout my two-and-a-half years there will live long in the memory as will everything else we shared in some of the ground-breaking successes we all enjoyed together during that period.
"I can readily assure my successor that they will inherit an excellent group of players and to each and every one of them could I also say a huge thanks for making my time with them so successful and so memorable - I wish them and the club every success in the future."
Inverness Caledonian Thistle have confirmed the departure of manager John Hughes.