Ramires put Di Matteo's men ahead in the first half and they seemed to be crusing to victory before Andy Carroll scored one and was millimetres from a late second in a vain rally
A quality-starved first half was punctured only after 11 minutes when Ramires capitalised on a series of Liverpool errors to burst down the right and slot into the net.
Drogba’s historic finish soon after half-time looked to have Chelsea comfortable, but Carroll came off the bench to slam home an emphatic finish shortly past the hour.
He thought he had pulled off an astonishing comeback in the 82nd minute when he powered a header at the far post, but somehow Petr Cech was able to claw it back before crossing the whole of the line, those few millimetres securing the Blues' triumph as they held off a furious final assault.
Kenny Dalglish opted to leave Carroll on the bench, Luis Suarez playing alone up front with the likes of Steven Gerrard and Craig Bellamy forward in support, while there was no place for stalwart defender Jamie Carragher.
Former Reds star Fernando Torres was named as a substitute for Chelsea, with Drogba chosen to lead the line, while Branislav Ivanovic parterned John Terry at the back and veteran Frank Lampard started.
After both sides spent the first 10 minutes acclimatising, an array of Liverpool errors allowed Chelsea through. Jay Spearing lost the ball in the centre, allowing Juan Mata into possession, who fed Ramires on the right. The Brazilian easily powered outside Jose Enrique before finishing calmly past Pepe Reina, who had committed to his dive far too early.
The Reds sought a quick response, some flowing football resulting in the ball falling for Bellamy just inside the Chelsea box. The Welshman hammered a fearsome snapshot but Ivanovic was on hand with a crucial block.
Both sides looked to attack as the halfway point of the first period passed, Salomon Kalou embarking on a mazy, unchallenged run into the Liverpool area before being caught out by Daniel Agger at the last minute.
The Dane himself then buckled swashes with his own powerful drive forward, but as he pushed on into the box, Enrique’s pass was hit slightly too hard, and the spark was snuffed out.
There was little more joy for either side, Suarez only able to stretch enough to tamely make headed contact with an inviting cross from Jordan Henderson five minutes before the break.
Chelsea opened the second period with a testing corner from Lampard, Glen Johnson displaying plenty of muscle to hold off Terry, though the Blues captain still got a desperate touch that flopped onto the top of the net.
They were on target five minutes later, though. Lampard had space to pick his pass with the Liverpool back line ahead of him, electing not to shoot but to play it in for Drogba on the edge of the area. The Ivorian took a touch and aimed through the legs of Martin Skrtel to roll his record fourth FA Cup final goal into the corner.
Dalglish threw caution to the wind by replacing the struggling Spearing with Carroll and the target man made an immediate difference.
Found by Enrique in the box, Carroll juggled and stepped over and seemed to have missed his moment to strike but instead whipped around the beaten Terry and slammed home left-footed to put Liverpool back in it.
The breakthrough woke the Reds up and they streamed forward, the substitute striker at the heart of it. His header down teed up Henderson to shoot wide from 20 yards as the crowd came alive.
Gerrard tried his luck next, attempting to meet a knock-down from over 30 yards out with a trademark howitzer, but he miscontrolled and fired wildly over the top. Carroll then came back into play as he met Enrique’s left-sided cross with a header not far off-target.
Liverpool thought the £35 million man had struck again in the 82nd minute, arriving superbly to blast a thumping header at the far post. Reds players and fans alike celebrated a goal but the referee's assistant made a superb call to point out that Cech had in fact jumped quickly enough with incredible reflex to keep the whole of the ball from crossing the whole of the line.
Dalglish's men hammered away in the final minutes with Chelsea clinging on desperately - although Skrtel had to cover for an exposed Reina at the death - but the final breakthrough just would not come and the Blues celebrated their fourth FA Cup triumph in six years.