It brought an end to their 12-match unbeaten run, during which David Moyes looked like he was finally growing into the job that he took on in the summer.
But the loss against his former club reopened all the cracks that were visible during United's shaky start to the season.
After 14 games, they have already lost four times and are as close to the relegation places as they are to league leaders Arsenal. A hectic December schedule is looking increasingly pivotal to Moyes' first season at Old Trafford.
Here are six things that we learned from the match.
1. Losing to Everton is an embarrassment for Moyes
Everton under Roberto Martinez will take points off plenty of big teams this season and will have a good go at finishing in the top four.
But losing to them at Old Trafford is an embarrassment for David Moyes. Everton under Moyes never won a Premier League game at Old Trafford in 12 attempts. They never won at Arsenal, Chelsea or Liverpool, either.
But Martinez has broken that run in his first season at Goodison Park, which suggests Everton's poor run had more to do with Moyes than his players.
2. You can't rely on 40-year-old Ryan Giggs
The plaudits rained down on Ryan Giggs on the occasion of his 40th birthday last week, and much of them were fully deserved.
But to leave a 40-year-old outnumbered in midfield in a Premier League game, especially against an in-form Everton, is too much to ask.
Paired with Marouane Fellaini in midfield, Giggs was overrun by Everton's midfield three of Gareth Barry, James McCarthy and Ross Barkley.
With Michael Carrick out injured and Phil Jones suspended, Moyes didn't have many options, and Giggs had played well last time out against Bayer Leverkusen in the Champions League. But asking Giggs to do the running of two men in midfield is demanding too much.
3. Danny Welbeck is not a wide midfielder
Danny Welbeck is a good footballer, but his attributes aren't suited to playing out wide. He's hard-working and diligent, but he's still a striker who is playing out of position.
With Wayne Rooney, Robin van Persie and Javier Hernandez in the squad, Welbeck will find opportunities up front hard to come by.
But playing him out of position isn't helping him or the team. Nani was far more dangerous when he was on the left against Everton, firing one wonderful cross into the box that was begging for someone to touch it into the net.
It's much the same situation with Shinji Kagawa. He was one of United's biggest threats in the first half, playing behind Rooney. Moved out wide in the second half, he was less effective and soon replaced.
4. United need more stability at the back
Moyes started the season with Rio Ferdinand and Nemanja Vidic as his first-choice centre-halves. When that started to crumble, he introduced Phil Jones and after that Jonny Evans.
Against Everton, Chris Smalling and Vidic manned the position. United have a wealth of options at centre-half, but Moyes has yet to decide on his starting pair.
And while it's beneficial to keep players fresh, there's a point when the constant state of flux is detrimental. The only member of the back four to nail down his place is Patrice Evra, whom Moyes tried to replace in the summer.
5. Moyes has got it in him to be adventurous
There have been question marks over Moyes' desire to win games rather than escape with a draw, but he at least showed a will to win against Everton.
With more than 30 minutes to go and the game still goalless, Moyes threw on Nani and Adnan Januzaj for Rafael and Kagawa.
They were two attacking substitutions. And although United ended up losing the game, Moyes at least showed that he wants to win tight games and is prepared to lose in the effort.
Granted, that will be little consolation for United fans in the aftermath of another home defeat.
6. Moyes' reception from the Everton fans was not mixed
Per BBC Sport, the United manager said before the game that he thought he would get a "mixed" reception from the travelling fans after leaving Everton after 11 years for Old Trafford.
It was nothing of the sort.
They roundly booed him when he walked out into the technical area for the first time and taunted him throughout. After Bryan Oviedo's winner, the volume increased as they sang, "Are you watching, David Moyes?" and "You're getting sacked in the morning."