Frank Lampard buried a penalty within just three minutes before heading in a second and Jermain Defoe's threaded finish put Roy Hodgson's men 3-0 up at half-time.
Coasting in the second half, James Milner and Leighton Baines both nonetheless scored their first international goals to complete a comfortable performance.
Hodgson followed through on his pre-match suggestion of pairing Lampard and Steven Gerrard in the centre of midfield, with Tom Cleverley pushed further upfield to play off lone striker Defoe. Leighton Baines made his first competitive start in place of the injured Ashley Cole.
With England immediately taking control of the game, they were handed a rather fortunate opportunity to secure an immediate lead.
Three minutes in, Cleverley’s shot hit the arm of Semion Bulgaru for a penalty, though the right-back had been so close to the Manchester United man that he could hardly have moved out of the way any quicker.
Lampard stepped up to score his eighth penalty in national colours, becoming the Three Lions’ most successful spot-kick-taker in the process, and the visitors were already comfortable.
Moldova looked in for a long evening, Defoe missing from close range after Alex Oxlade-Chamberlain’s enterprising run and cut-back before goalkeeper Stanislav Namasco saved well from both players.
The hosts got hold of the ball enough to go forward for the first time on 18 minutes, Artur Patras picking up possession around 25 yards out and firing while he had the chance. His effort flew just close enough to warn England that the job was nowhere near done.
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Glen Johnson advanced for Hodgson’s flowing side and, being left unchallenged, took the opportunity to cut inside and shoot low with his left foot. Namasco let it slip but Moldova cleared just in time.
The putting-down of Moldova’s mini-resurgence in confidence was sealed when Johnson spotted Lampard’s trademark late run into the box and picked the midfielder out with a fantastic cross, which the Chelsea man headed in with no trouble for his second.
With a sense of inevitability now blanketing proceedings, Cleverley flashed inches wide as he aimed to open his international account, but Defoe had better luck moments later when he ran intelligently into the path of an Oxlade-Chamberlain pass to fire home, though Namasco should have done more than let it slip through his hands.
As England coasted and broke out the tricks, Moldova arguably should have struck back just before half-time. From a rare set-piece, Igor Armas rose strongly above the defence but headed barely wide.
With Gerrard withdrawn for Michael Carrick at the break, England were made to raise an eyebrow when Igor Picusciac held off his marker in the box to shoot, though it was easily off target.
England were relaxed and Patras was allowed space into which to run after 53 minutes but, frustratingly for the hosts, his attempted through-ball was into the path of the defenders rather than Picusciac.
It became clear that the visitors had slowed with complacency and Moldova had time to build. They were unlucky when a prolonged catalogue of poor passes from either side ended in Serghei Covalciuc miscontrolling and letting England off the hook.
The visitors now sat and waited to counter, the impressive Oxlade-Chamberlain substituted for Theo Walcott to add more threat down the right, but increased possession at the back did little for Moldova’s penetration up front.
Cleverley reminded them of England's superiority by cutting a shot wide from the left in the 66th minute but Hodgson's men were now assuredly quiet.
As the away side coasted, Danny Welbeck was introduced for Defoe and his patient combination with Cleverley and Walcott forged space for the latter to pull it back for Milner, who thumped home a fourth.
The pressure off, Moldova kept coming forward and won the occasional corner, Patras looking useful in the delivery and Joe Hart even having to make a routine save, but hope was long gone.
A torrid night for the hosts was compounded by Baines' 83rd-minute free kick taking a huge deflection off the shoulder of a man in the wall before dropping into the net, the streakiest of first international goals for the nonetheless-delighted left-back.
Perhaps England's only concern of the evening was when John Terry, having tried to shake off an injury, gave up and came off to leave them with 10 men for the final moments. Questions now will surround his fitness to face Ukraine but it will have been one of the only questions after a comprehensive victory was confirmed by the full-time whistle.