Frank Lampard got the ball rolling against their Group H opponents by converting a penalty on four minutes after Semion Bulgaru was booked for handling Tom Cleverley's shot inside home area.
It was a harsh decision by the Dutch referee Pol van Boekel, but Lampard slammed the ball low and hard to his left to leave goalkeeper Stanislav Namasco with no chance.
Lampard added the second when he sped into the box to head Glen Johnson's cross into the home net on 29 minutes before Jermain Defoe buried the second from an inventive pass by Alex Oxlade-Chamberlain three minutes later.
Namasco should probably have prevented Defoe's effort from hitting the rigging, but a 3-0 lead hardly flattered the visitors at half-time.
Interestingly enough, Lampard's last two goals in a game for England came against Croatia in 2009; the first was a penalty and the second was a header provided by a Glen Johnson ball.
James Milner added the fourth on 74 minutes after nice passing play before Leighton Baines saw a deflected free-kick loop into the net from 25 yards out to complete the scoring on 83 minutes.
The last time England scored five goals in an away international was in a 5-1 win in Germany in 2001. This was not entirely unexpected coming against a side ranked 141st in the world.
England have now been awarded 100 penalties in their history – scoring 69 and seeing 31 saved or missed. Lampard has scored eight of these – more than any other England player.
England will certainly have a tougher time in their next assignment as they fly home to prepare for the visit of the Ukraine. They play the Euro 2012 co-hosts at Wembley in the second of 10 qualifying matches for the finals in Brazil on Tuesday evening.
The only negative of the night was seeing John Terry forced off with four minutes remaining due to an ankle injury. Roy Hodgson concedes he may miss the match against the Ukraine.
Hodgson opted to start with Lampard, Cleverley and Steven Gerrard in his midfield and was afforded the luxury of replacing Gerrard with Michael Carrick at half-time as England largely finished off their work for the night in the opening half.
England occupy a lofty third place in the FIFA standings and seemed to have the freedom of a quaint ground in Chisinau that gave off the feel of an FA Cup tie, but proved to be routine for the visiting side.
Defoe almost added a second goal to go with Lampard's first on 10 minutes when he knocked the ball wide from an Oxlade-Chamberlain pass with Namasco diving to claw out a Defoe shot moments later.
Namasco was forced to repel a volley by Oxlade-Chamberlain on 13 minutes while Gerrard walloped a shot narrowly over from a rolled Lampard free-kick on 22 minutes as England continued to excel.
Namasco halted a Johnson shot on 26 minutes while Moldova's best chance of the match fell to Igor Armas seconds before half-time when he headed wide from Sergei Kovalchuk's cross.
England did not need to get too flustered in the second period as Milner added the fourth goal from 15 yards after Cleverley, Danny Welbeck and fellow substitute Theo Walcott had led Moldova a merry dance in their own penalty area.
Baines's free-kick found the net from distance via the shoulder of Alexandru Gatcan. It was a fortunate fifth goal, but England were mostly convincing.