Atalanta scored twice in four minutes to deliver a surprise victory over Liverpool and blow qualification from Champions League Group D wide open.
A much-changed Reds side lacked fluidity and failed to have a shot on target at Anfield on Wednesday.
Josip Ilicic and Robin Gosens struck for the Serie A side midway through the second half.
Mohamed Salah, returning to the side, had fired over with the Reds’ best chance in the first half.
The Italian outfit looked more likely to break the deadlock and did so when Ilicic poked beyond Alisson from Alejandro Gomez’s teasing cross.
The visitors doubled their lead four minutes later when an unmarked Gosens volleyed in from Hans Hateboer’s nod down.
Liverpool manager Jurgen Klopp immediately made four substitutions in a bid to get something from the game, but the changes could not prevent the Reds suffering their first home defeat inside 90 minutes since September 2018.
Klopp’s side still remain top of the group and need one win from their final two games – at home to Ajax and away to Midtjylland – to qualify.
Klopp will surely be disappointed not to have wrapped up his side’s qualification for the knockout stages and given himself the opportunity to rest players.
The German has already bemoaned the fact his team have to visit Brighton at 12:30 GMT on Saturday, urging broadcasters to discuss the schedule or risk clubs losing players to injury.
It is also no secret the Reds are already without a number of first-team regulars, and with Curtis Jones, Rhys Williams and Neco Williams in their line-up, Liverpool became the first side to start three British teenagers in a Champions League match for more than a decade.
Klopp made five changes to the side that beat Leicester City on Sunday, including Salah, who returned after his positive Covid-19 test while on international duty with Egypt.
On an off night for the Reds, Salah, who earlier in the day was named on the shortlist for the men’s prize in the Best Fifa Football Awards, engineered the hosts’ only real chance when he shot over in the 44th minute.
Liverpool lacked their usual intensity and even the arrival of Roberto Firmino, Diogo Jota, Andrew Robertson and Fabinho after 61 minutes failed to inspire any urgency.
Instead, they were deservedly beaten by an Atalanta side they had inflicted a 5-0 defeat upon earlier this month.
Atalanta impressed as underdogs on their Champions League debut last season, only missing out on a semi-final spot when Paris St-Germain progressed in dramatic late fashion.
But the Bergamo outfit headed to Anfield without a win in all competitions this month, including that thrashing by Liverpool in Italy.
They looked a different side during Wednesday’s victory, limiting the Reds to just three shots, none of which troubled goalkeeper Pierluigi Gollini.
Diminutive captain Gomez dictated the play for the visitors and it was the Argentine’s inswinging cross that found forward Ilicic to break the deadlock.
Another Gomez delivery from the left picked out Hateboer and he guided it into the path of the impressive Gosens in space on the edge of the six-yard box to finish.
“Obviously this is something which will be written in the pages of history,” said coach Gian Piero Gasperini. “This is perhaps our biggest ever victory in our history, certainly our most prestigious.”
The Serie A side have now given themselves a shot at qualification for the last 16, hosting Midtjylland next before a visit to Ajax in a match that may be a decider for who progresses.