There was quiet optimism that the Red Devils could secure another dramatic Champions League comeback, but they were soundly beaten at the Nou Camp on Tuesday night.
Despite producing some threatening moments during the opening exchanges, Barcelona quickly asserted their dominance and Lionel Messi was keen to pounce on any and every opportunity.
The magical Argentine opened the scoring after just 16 minutes, finding the bottom corner with a superb left-footed finish after taking advantage of a defensive error.
Messi was even more fortuitous when it came to his second goal, profiting from a mistake by De Gea, who failed to hold a tame right-footed strike.
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Barcelona 3-0 Man Utd
His gaffe would ultimately hammer the nail in United's coffin, before Philippe Coutinho put the game out of sight with an incredible effort during the second-half.
Although De Gea has produced a number of brilliant saves this season - most recently during the West Ham victory - he has arguably dropped the most errors since his initial United move.
The 28-year-old was lambasted in Spain for his performances at the World Cup, while mistakes have also surfaced during games with Arsenal and Switzerland.
Mistakes vs Messi and Ronaldo
However, his error against Messi is perhaps the most high-profile since he fumbled a Cristiano Ronaldo shot into his own net in Russia last summer.
It's perhaps uncanny that De Gea has conceded two soft goals from the most lauded players in the sport, both on their weak foots, in the matter of nine months.
There's definitely some similarities between the two mistakes, too, so it shouldn't come as a surprise that somebody has cut the respective gaffes together.
Check out a comparison of the goals down below:
Oh dear, David.
For all his shot-stopping brilliance and claims as the best goalkeeper in the world, De Gea seems to be more susceptible to mistakes than ever and it's certainly worrying for the fans.
Had De Gea held on to that shot from Messi, it would have allowed more time for United to potentially open their account in Catalonia and get themselves back into the game.
One goal wasn't a disaster for Ole Gunnar Solskjaer and his team, but a quick-fire brace for Messi left them needing to climb Everest to restore their European hopes.
You can certainly argue that De Gea's brilliant saves cancel out the errors, yet there's definitely room for improvement to be more consistent this season.
Either that or he simply can't figure out Messi and Ronaldo when they use their weak foot.
Do you think De Gea is the best goalkeeper in the world? Have your say in the comments section below.