Even with the influential Irishman in their back line, United had one of the most pourous defences in the Premier League. Without him, the task of overhauling the 14-point, and three-team, gap to survival will be even harder in the 14 matches that remain.
All teams suffer injuries, and all teams' fans think that they are harshly treated by The Footballing Gods. And although it’s not solely to blame for their position in the table by any stretch, United do seem to have been especially hard done to this season.
Here are some of the main injuries they have suffered this campaign, and how they have affected Chris Wilder's men...
Jack O'Connell (knee)
There is no shortage of theories amongst pundits, fans and general observers as to why United have struggled so much this season.
"They've been found out," cry some. Many blame the mythical 'second season syndrome' that is defied more often than it comes true.
Others - including Karen Carney, whose intelligent and knowledgeable BT Sport punditry on United's defeat at West Ham was decried by many on social media, because she happens to be a woman - point to the loss of O'Connell, whose knee problems resulted in surgery and a dramatic drop-off in United fortunes.
Anyone who has watched United at any length over the last few years will know how integral O'Connell is to their fortunes. He is a very rare player indeed - with a boxer-like build and will to win like some at United have never seen before, but also possessing the skills to make him a headache for opposition defenders too.
Without him, United's famed system of overlapping centre-halves is diluted massively. United have become easier to play and score against, and it's tempting to wonder how many of the goals they have conceded from set-pieces this season would have gone in if O'Connell was around.
The sheer number of players who have played in his position alone shows how difficult he is to replace and if United are relegated this season, that must surely be taken into consideration if, or more likely when, bids start to circulate for his services.
John Fleck (back)
At the time, not many outside Bramall Lane's inner circle realised how serious it was when Fleck went on international duty with Scotland, suffered an awkward fall and missed a chunk of his club's games in the weeks that followed.
It was only later in the season that Fleck himself revealed that he had actually broken his back in the fall, which perhaps explained both the length of the absence and the fact that the midfielder didn't seem to be at full fitness for a while when he eventually came back.
Ben Osborn, who deputised for Fleck, is a good player. Tenacious off the ball and capable of showing moments of quality on it. But like O'Connell, Fleck has been such a key player down the left hand side for the Blades and suddenly, someone like Enda Stevens - so well-versed in creating those overloads that he could probably do it in his sleep - looked up and saw neither O'Connell or Fleck available to bounce off.
It's no coincidence that Fleck's recent return to form came around the same time that the Blades started to pick up form, and all at United will hope to see him back in the squad sooner rather than later as he recovers from a mystery virus that saw him hospitalised at the weekend.
Sander Berge (hamstring)
Wilder's recent interview with Norwegian TV all-but confirmed that Berge will not remain at Bramall Lane if the Blades are relegated this season and sections of the United fanbase have already resigned themselves to the fact that they may never see him in a Blades shirt again.
The Norwegian damaged a hamstring against Manchester United, later going under the knife to correct the problem, and Wilder doesn't expect to have him available again until April.
At the time he got injured, Berge had been United's most impressive performer of the season. He was playing in a struggling team and in an unfamilar position, often on the right of midfield rather than at the base of it, but his ability shone through as he drove forward with the ball, his long arms and legs flailing everywhere and keeping opponents well at bay.
His absence, and the lack of any arrivals in January, meant that United often went into games in recent weeks without a senior midfielder on the bench and with Fleck missing at West Ham, 17-year-old Frankie Maguire was drafted onto the bench.
Whatever your views on Berge, the fact that Chris Wilder made him the most expensive player in United's history last January shows his faith in the midfielder. And as they rallied against relegation, having one of their best players sitting on the sidelines has not helped United one bit.
Enda Stevens (various)
After playing 44 games for club and country last season, it's been a stop-start campaign for Stevens down the left side of United's defence this time around and a backline that was so remarkably consistent last season has been chopped and changed seemingly by the game. And not by the manager's choice, either.
He missed a chunk of games in November and December with a knee injury, and has only just returned to the United side after a calf problem kept him out for almost a month.
At times last season Stevens was unplayable, with the club's media team producing compilations of him nutmegging opposition right-backs for fun. But he has struggled to replicate those heights with injuries disrupting his season, as well as the loss of O'Connell and Fleck at different parts of the season.
That left United relying on either Max Lowe, Osborn or Kean Bryan at left-back and on one occasion, when all three were struck down by injury issues, right-back Jayden Bogle had to fill in - at Manchester City away.
George Baldock (hamstring)
No injury can be seen as a positive, but Baldock's spell on the sidelines was mitigated by the emergence of Jayden Bogle, who has been a rare chink of light in an otherwise depressing season.
But Baldock was another impressive performer last season, playing every single minute of Premier League action for the Blades, and the sight of him limping off just before half-time of United's clash with West Brom rather typified United's luck this season.
Oli McBurnie (shoulder)
The Scottish international damaged his shoulder in a challenge away at Southampton, capping another miserable day for the Blades as they were soundly beaten, and despite coming off the bench on Boxing Day against Everton, wasn't seen again until the end of January.
In mitigation, the striker department is one that United have quite well-stocked. But without McBurnie they missed a focal point if they needed it, and a physical threat to win flick-ons and headers against centre-halves.
McBurnie is also a better player than many give him credit for with his feet, and helped turn the game around after coming on at half-time of United's win over West Brom earlier this month.
Lys Mousset (various)
On his day, Mousset is a real handful for opposition defenders and during his purple patch last season, when he scored four vital goals in six games, it looked like the money United had paid Bournemouth for his services looked a real bargain.
For most of his time at Bramall Lane, though, the Frenchman has flattered to deceive. A personal issue saw him return home to France after lockdown last season and just as people at Bramall Lane were beginning to predict a big season for the striker, he was injured in pre-season and didn't play until the end of November.
Since then he has made just six more appearances, the last coming in the FA Cup against Bristol Rovers, and he didn't even make the squad at the London Stadium, despite being fit enough to take his place amongst the substitutes for the FA Cup win over Bristol City a few days earlier.
Mousset has not stepped up for United often enough since he joined and judging by Wilder's last mention of him in a press conference, patience is beginning to wear thin.
“There’s two parts to Lys,” Wilder said, acknowledging Mousset has also suffered from bad luck at times.
“There’s our part as a club in terms of getting to the bottom of the issues and there has to be a really big effort from the player, to push and participate.
“We’re not chucking him under the bus. He knows how we view him and that we like him. But Lys needs a big second half of the season. I want it to happen but he has got to want it to happen as well.
“There are things that he can do better.”