The radio and television producer said he was leaving the show to concentrate on his film career.
He said it was "with a heavy heart" that he said goodbye to Albert Square.
Before joining the square in Walford, O'Connor was the editor of BBC Radio 4's The Archers, and was responsible for the domestic abuse story between Helen Archer and Rob Titchener.
O'Connor said: "I've had an amazing time at EastEnders.
"I'll enjoy watching EastEnders go from strength to strength but will miss everybody enormously. Elstree really is a place where you make friends for life."
He added that he had intended to continue at Elstree - the Hertfordshire studios where EastEnders is filmed - until the end of 2017.
But filming commitments with Camberwell Productions meant his departure came sooner.
Along with other projects, O'Connor is moving to work with Sherlock co-creator and League of Gentleman star Mark Gatiss.
Gatiss is writing his first big screen feature on the murderer Neville Heath.
Controller of BBC Drama Piers Wenger said: "I want to thank Sean on behalf of the BBC for the work he's done on EastEnders, and we wish him all the very best for the future."
Former Channel 4 head of drama John Yorke will take over as temporary creative director.
He was previously executive producer on EastEnders between 2000 and 2003, during the time that Phil Mitchell had been shot by his girlfriend Lisa.
Head of continuing drama series at BBC Studios Oliver Kent said: "John Yorke is a Walford legend and I am thrilled that he will be joining us for a short period to oversee the show and to help us build on Sean's legacy while we recruit a long-term successor."
EastEnders executive producer Sean O'Connor is leaving the long-running soap after a year in the job.