The holders and winners for the past two seasons appeared to be heading for a fourth-round exit at Everton after falling behind to a Louis Saha header. The forward pulled off his marker John Terry at a corner and planted a header beyond Petr Cech.
Chelsea responded well to slipping behind and a rapid break saw substitute Kalou, who had been on a matter of minutes, beat Tim Howard. It came just moments after Petr Cech had produced a brilliant save to prevent Seamus Coleman doubling the Toffees' lead.
There were chances for both sides to win the game, Ramires fizzed a shot against the post for Chelsea and Jermaine Beckford forced a superb save out of Petr Cech, but they will have to do battle again at Stamford Bridge.
Michael Owen and Javier Hernandez teamed up to spare Manchester United's blushes as League One Southampton threatened to pull off a major giant-killing act.
The Saints took the lead in stunning fashion on the stroke of half-time when Richard Chaplow surged into the penalty area from the right and smashed an unstoppable shot past debutant keeper Anders Lindegaard to rekindle memories of their famous 1976 final victory over United.
However, the Barclays Premier League leaders got themselves back on level terms 20 minutes into the second half when Michael Owen met Gabriel Obertan's right-wing cross to head home, and Hernandez dispensed with the need for a replay with the winner 10 minutes later to seal the 2-1 win.
Crawley Town became only the sixth non-league team to make the Fifth Round since the war - no team has gone further in this period - as they won 1-0 away at League Two side Torquay United.
Matt Tubbs fired the visitors ahead six minutes before the break, and after the Gulls had Chris Zebroski sent off for a second bookable offence, Tubbs and team-mate Craig McAllister had second-half penalties saved by Scott Bevan.
Crawley had defender Dean Howell sent off in the 83rd minute and almost paid the price late on when defender Kevin Nicholson crashed a shot against the crossbar, but they managed to hang on to claim a place in the last 16.
Swansea defender Alan Tate put through his own net in the 88th minute to hand Leyton Orient a 2-1 win and passage into the FA Cup fifth round for the first time in 29 years.
Jimmy Smith headed Russell Slade's men ahead in the 35th minute, but the Swans levelled on the stroke of half-time through Cedric Van der Gun.
Yet the real drama was still to come as Tate diverted a cross from substitute Paul-Jose M'Poku into his own net to send the League One club into the next round.
Birmingham showed tremendous fighting spirit to battle back from two goals down to claim a 3-2 win over Coventry at St Andrew's. The Sky Blues were two up inside 25 minutes through Marlon King and Richard Wood, but David Bentley sparkled the comeback with his first goal for the club.
Calvin Zola scored a debut goal for Burton, but it was not enough for the minnows to pull off a shock as two goals from Chris Eagles and a late strike from Martin Paterson helped Eddie Howe's Burnley claim a 3-1 win.
Stevenage, conquerors of Newcastle, saw their FA Cup dream end at home to Reading, but they put up a spirited display before falling 2-1. Mikele Leigertwood rifled the visitors ahead, but Stevenage raised hope of another upset when Darius Charles levelled 18 minutes from time.
They failed to find a second breakthrough and they were left reeling when Shane Long volleyed home a cross from Jobi McAnuff four minutes from time.
Sheffield Wednesday rallied from the shock of falling behind at home to Hereford to claim a 4-1 win at Hillsborough - Cliniton Morrison bagging two of the goals from the penalty spot.
Watford have been free scoring in the Championship, but they drew a blank at home to Brighton and it cost them as the south-coast side claimed a 1-0 win courtesy of an early strike from Ashley Barnes.
Premier League sides and North-West rivals Bolton and Wigan will have to go through a replay after playing out a 0-0 draw at The Reebok.