With the game goalless, Karius attempted to throw the ball out only for it to strike Real Madrid's Karim Benzema, who found an empty net to open the scoring.
Former players including Rio Ferdinand and Gary Lineker were among those to comment on Karius' ridiculous mistake.
Former Manchester United defender Ferdinand seemed shocked by Karius' mistake, while Lineker remarked: 'What an extraordinary error from Karius. Intelligent from Benzema but wtf?'.
Karius attempted to throw the ball to his team-mate Virgil Van Dijk but Benzema took advantage of his mishap to put Real in the lead.
Ex-England cricketer Michael Vaughan also had his say on the incident. He wrote: 'Karius will receive the Freedom of Manchester on Monday at a civic reception !!!'
Karius went on to make another high-profile mistake later in the game as he was unable to hold Gareth Bale's shot, which made it 3-1.
It was the goalkeeper's first error, however, which received the most criticism.
One user, El Jefe, called it the 'stupidest goal ever', with Karius' blunder leading to the goalkeeper receiving much criticism on social media.
MUFCHolic questioned comparisons between Karius and David De Gea, which had been made by some Liverpool fans earlier in the season. He wrote: 'Remember when they said Karius was better than De Gea because he played well for a month?'
Another user, Loso, wrote: 'Even if Liverpool win Karius cannot show his face in Liverpool after tonight'.
Meanwhile, MFinzi tweeted: 'Imagine travelling all the way to Kiev to have Karius make the biggest mistake of his career. Actual tears.'
Karius arrived at Liverpool from Mainz in 2016 and endured some difficult moments early in his spell at the club as he made some high-profile mistakes.
The 24-year-old has shown some significant signs of improvement this season and firmly established himself as Jurgen Klopp's first-choice goalkeeper ahead of Simon Mignolet.
However, Karius' major error on the biggest stage in club football certainly won't be forgotten in a hurry.
Some of the tweets are below:
Source: Daily Mail