Just three days after beating Liverpool 2-1 in the FA Cup final at Wembley, Chelsea were 3-0 behind inside half an hour at Anfield following an own-goal from Michael Essien and goals from Jordan Henderson and Daniel Agger.
Ramires scored for Chelsea early in the second half before Jonjo Shelvey ended any hope of a comeback with his first Premier League goal.
England's top four clubs will enter next term's Champions League unless Chelsea beat Bayern Munich at the German club's ground in the final on May 19.
If Chelsea win, it will deprive the team in fourth of a place in the preliminary round.
This defeat meant the top four was beyond the reach of Chelsea, who will now finish in sixth spot, as it left them five points behind fourth-placed Tottenham with just three on offer for beating already relegated Blackburn in their final league match of the season on Sunday.
"I think Liverpool were better tonight," Chelsea interim manager Roberto di Matteo told Sky Sports.
The Italian defended his decision to make eight changes from the team that ran out at Wembley by saying: "We've come so far because we've used the energy and players we have in the squad.
"That is the only way to be in the race until now. I have no regrets," the former Chelsea midfielder added.
"We've had very intense games and to get yourself up for all those has been a big demand. I thought tonight fresh legs would give us a better chance.
"We've got a game on Sunday and we want to finish our last game well to go into the Champions League final in a positive mood."
Victory, in their final home league game of the season, took Liverpool into eighth place but, despite a League Cup final win over second-tier Cardiff this term, no-one knows better than Reds manager and Anfield great Kenny Dalglish that more is expected of the Merseysiders.
"The players and everyone will be happy we ended on a high note," said the former Liverpool and Scotland striker.
"That performance was on a par with many this season but we've not had the results those deserve.
"For us it is a satisfactory evening and I hope the supporters go away happy. I don't think there are many other places where supporters would turn up and be so supportive, especially after the Cup final," Dalglish added.
The Reds' first three goals came in a dramatic nine-minute burst.
Essien put through his own net after a brilliant 19th minute run and cross by Liverpool striker Luis Suarez before Henderson capitalised on a slip by Chelsea captain John Terry to slide the ball home.
Then Agger, after Chelsea failed to clear a corner, headed in from close range.
Liverpool's Stewart Downing then saw his first half stoppage-time penalty hit the post before Ramires, who scored Chelsea's opener at Wembley, pulled a goal back for the visitors early in the second period.
But Liverpool were 4-1 up restored their three-goal lead in the 61st minute when Chelsea reserve keeper Ross Turnbull, making a rare appearance in place of Petr Cech, miscued a clearance from outside his box straight to Shelvey and the midfielder steered the ball into an empty net from 30 yards.