Horan confirmed the decision less than 24 hours after the eight-point loss, bringing to an end a second four-year term.
In 2014 he also stepped away within hours of their semi-final replay loss to Kerry in Limerick.
Horan returned after four years away in late 2018 and brought Mayo to two All-Ireland finals which they lost to Dublin and Tyrone in 2020 and 2021.
But this year has been disappointing and while his credit line over most of the eight years he has been in charge would have been strong enough for another year if he wanted it, they now look like a team best served with a chance of direction and voice at the helm and ultimately Horan has recognised that.
Mayo didn't have much luck with injuries over the last two seasons especially with both Tommy Conroy and Ryan O'Donoghue missing for recent championship games.
Last year Cillian O'Connor ruptured an Achilles tendon that has left him playing catch up with fitness and form.
The development of Conroy, O'Donoghue, Oisin Mullin, Eoghan McLaughlin and Matthew Ruane on his watch were arguably his biggest successes while the extra--time win over Dublin in last year's All-Ireland semi-final was the obvious high point.
But repeated failure to make their dominant spells count, in evidence again last Sunday and a failing of so many Mayo teams in the past, ultimately denied them.
Horan issued a statement earlier to confirm his departure.
"Now that the season has drawn to a close and my second four-year term as Mayo Senior Football manager has been completed, I am stepping aside from Mayo football," he said.
"It has been a brilliant journey and I feel very lucky to have worked with great players and people during that time. We had some great times and created brilliant memories that will live on.
"The initial focus was to make Mayo football consistently competitive on the main stage, I feel that has been achieved and the senior team have moved in the right direction.
"Hopefully, there is a strong base for Mayo football to be moved forward to new heights. I have worked with some amazing people over the last decade from Support Teams right through, there are too many to mention here, but I will ensure every one of them understands the tremendous contribution they have made to their county.
"Also, the Mayo supporters that followed the team through thick and thin were brilliant and the support we as a team have received over the years has been fantastic. But most importantly it’s the players that represent Mayo we all should be very proud of.
"They are brilliant ambassadors for our County and have a spirit and togetherness that will keep Mayo football moving forward. Lastly to my family who have been incredibly supportive over the last eight-plus years, a huge thanks,” commented James Horan.
Mayo chair Seamus Tuohy thanked Horan for his efforts. "James has given it everything and while the ultimate reward did not arrive, he cannot be faulted for his effort. Mayo have been consistently competitive under James and we have come agonisingly close on so many occasions. I regret his departure but appreciate the huge sacrifices he has made over this period."
Mayo will now begin the process of finding a new manager. Knockmore's back-to-back county title winning manager Ray Dempsey could be a contender while Kevin McStay's name will be part of any potential list of candidates though McStay did stress when he departed Roscommon in 2018 that he would not be returning to inter-county management.
Andy Moran has spent a season managing Leitrim and while he is not long out of the dressing-room, a return to his native county to work with some of those players could be too tempting.