Back-to-back games against Manchester's finest always looked like a yardstick for Tottenham's progress in the wake of the world record sale of Gareth Bale to Real Madrid and a raft of expensive new signings in the close season with the proceeds.
But few would have predicted the Portuguese would find himself as the bookmakers' favourite to get the sack.
"It all looked good for AVB at the end of October but in a month Tottenham have turned from title contenders into a team clinging on to the top 10," said a spokesman for betting firm Paddy Power, which slashed odds on his exit to 10-11 on.
"Common sense should prevail and the young manager should be given time but this is the bonkers world of Premier League."
Last Sunday's 6-0 drubbing at City was Tottenham's worst defeat since 1996 and while they are only two points off the top four there is growing frustration at the time it is taking Villas-Boas to get his new-look side to click.
"I have the confidence of the board and players and I have to move on to do a proper job," the Portuguese told a news conference.
"I am immune (to criticism) right now. I used to read a lot into situations like this, into pressure points when I was at Chelsea, but not any more. I am very indifferent."
After being axed by Chelsea, Villas-Boas resurfaced at White Hart Lane last term and earned plaudits as Tottenham came fifth with 72 points - the club's highest Premier League total - but just failed to earn a Champions League spot.
This season, despite the additions of Brazil midfielder Paulinho, Spain striker Roberto Soldado, record signing Erik Lamela of Argentina and Denmark playmaker Christian Eriksen, Spurs have managed only nine goals in 12 league matches.
A mean defence has kept them in and around the top four but things unravelled in spectacular fashion at City.
United may not have been setting the world alight either under new manager David Moyes but they are unbeaten in six league games and have not lost at Tottenham since 2001.
Wednesday's qualification for the Champions League last 16 after a 5-0 away thrashing of Bayer Leverkusen has also boosted confidence.
Spurs did win at Old Trafford last term for the first time since 1989 - a result that proved the springboard for Villas-Boas's encouraging first season at the club - but their record against United in recent years is woeful.
Tottenham's cause is hardly helped by Thursday's trip to the Arctic Circle to face Tromso in the Europa League, while United have an extra day to prepare.
Spurs have lost two of their last three home league games and only beat Hull City with a questionable penalty.
Former Tottenham midfielder Graham Roberts believes Villas-Boas must decide quickly on his strongest side.
"I wish he wouldn't swap the team around so much," Roberts told radio station Talk Sport. "We haven't had the same team two games running.
"If you are going to get players knowing how they play with each other, to get that connectivity, you need to play your best team but he doesn't seem to know what it is."
Tottenham's Belgium defender Jan Vertonghen said facing United could work in their favour.
"We can solve the problem. We will talk and bounce back on Sunday against Manchester United," he said this week.
"It is a good thing we play United next at home. I know we have the support of our crowd and we can win that game."
While Spurs toil, neighbours Arsenal go from strength to strength with Jack Wilshere scoring twice in a midweek win over Olympique Marseille that put the Gunners on the brink of reaching the last 16 in the Champions League.
Arsenal can go seven points clear of the Premier League pack with victory at Cardiff City on Saturday, a fixture that will see in-from Wales midfielder Aaron Ramsey return to the club where he began his career.
"We've created a fantastic opportunity for ourselves in the early part of this season and hopefully we can continue that," Ramsey, who has scored 11 goals this term, told Walesonline.
Arsenal will be wary of the Welsh side, however, after they beat Manchester City and drew 2-2 with United last week.
Second-placed Liverpool visit Hull on Sunday when stuttering Chelsea, who are third, host fifth-placed Southampton.
Swansea City will travel to Manchester City with a fair degree of trepidation on Sunday.
Manuel Pellegrini's City side have scored 13 goals without reply in their last two home games and have a 100 percent record there in the league this season, scoring 26 goals in six games.