It's a huge blow to a side who were intent on retaining the Premier League crown they won in the summer.
Joel Matip and Joe Gomez are now the first-choice pairing at centre-back for Jurgen Klopp but the Reds boss must now be rueful he was unable to sign a defender to replace Dejan Lovren.
The Croatian left in the summer, along with Ki-Jana Hoever, and Van Dijk's anterior cruciate ligament now leaves them incredibly light at the back.
Sepp van den Berg and Nathaniel Phillips are options for Klopp as backups, along with Rhys Williams who started alongside Van Dijk in the Carabao Cup against Lincoln.
But despite this thin defence, Liverpool, realistically, should have no problems at all in retaining their trophy thanks to the quality still available to Klopp and talkSPORT can tell you why below.
*All stats correct on October 19, 2020
Alisson will return soon
Were you to team up Van Dijk's injury with a lengthy absence for the Brazilian shot-stopper then there might be a real issue.
Klopp, though, appears positive about his prognosis and there is a suggestion he could even be back to face West Ham on October 31.
Alisson may have only played in three Premier League matches this season but he's already been in fine form, outperforming his post-shot expected goals.
According to FBref, with data provided by StatsBomb, an average goalkeeper would have conceded 4.8 goals in the trio of games instead of the four he actually allowed into the back of his net.
It's the second best record in the top flight so far, behind Aston Villa's Emiliano Martinez but more importantly, way better than his replacement Adrian.
The Spaniard has under performed by 1.9 goals, conceding almost a goal per game more than he should have.
Alisson's return will be crucial to the Reds coping without Van Dijk.
At the other end of the pitch, the Reds have got it covered.
Losing the domineering Dutchman is a huge blow but when you take a breather and consider the stunning strike force they have, Liverpool should be able out-score anyone.
It's a bit Fat Les, but 'we're gonna score one more than you' might have to be the mantra in this chaotic Premier League season.
Already, across five games, Klopp's side have racked up 13 goals - the joint-third most in the division, behind only Tottenham (15) and Everton (14).
When it comes to expected goals (xG) they have outperformed every team - even free-scoring Spurs - with stats suggesting they should have netted 12.9 times - so they're actually doing about right in front of goal. Perfect, no regression to fear.
Meanwhile, they might be conceding more xG (8.9) than they would want - it's the fifth worst in the division - but even so, they have the best xG difference of any side.
It could be a wild ride without Van Dijk but the Reds should still be able to defeat opponents thanks to the skills of Sadio Mane and Mohamed Salah.
Mane is hovering around his xG, netting four times when stats suggest he would have got around 3.4 in his opening fixtures, Salah, on the other hand, is out performing his thanks to a couple of penalties.
And to complement the goalscorers up top, the Liverpool playmakers are doing the business getting the ball into the right areas of the pitch.
Already this season, they have racked up almost 3000 more yards of progressive passing than any other team - the closest being Chelsea, Everton, and Tottenham, while they have also made 64 key passes, 11 more than nearest rivals Spurs.
It's promising, and it gets even better with Liverpool getting passes into the final third more than any other team - on 230 occasions, 33 more than Man City - while they have completed 71 into the penalty area, 20 more than anyone else.
If Klopp can keep his midfielders - and his full-backs - on this pace, not much can realistically stop the Reds' title charge.
Tenacity across the pitch
It's not just with the ball Liverpool are excelling already this season.
They have won the sixth most tackles, more than any 'Big Six' team, they have attempt more tackles than anyone in the final third, and the second most in the middle third.
Combine that with their elite pressing, 305 final third pressures - 97 more than second-place Spurs - and the fact they're the sixth best side when you combine the number of players tackled and interceptions, they should be able to halt opposition before they even get to their Van Dijk-less backline.
But there is one big problem…
Liverpool have been sensational, and one of the big reasons behind that has been the fact their standard never dropped.
However, errors which directly lead to shots are creeping into their game.
Last season they only made 10 in total, three years ago it was just nine, while in 2018/19 they did move up to 14.
In 2020/21, with just five games gone, though, they have already made five errors - the joint most along with Chelsea.
Tottenham, meanwhile, haven't made a single one yet, while Manchester United have only made one and Man City two.
You can listen to commentary of Liverpool v Sheffield United on Saturday, October 24 at 8pm - live on talkSPORT
Liverpool face an uncertain season with top defender Virgil van Dijk now ruled out for the foreseeable future.