After Steven Gerrard opened the scoring with his 20th international goal, a Rickie Lambert header and a Danny Welbeck brace completed a win that saw England overtake former leaders Montenegro on goal difference.
Welbeck's superbly taken double took his tally to six goals in seven international games, but he also picked up a booking that rules him out of Tuesday's key game away to third-place Ukraine, who trail England by a point.
With Wayne Rooney, Daniel Sturridge and Andy Carroll injured, and Jermain Defoe short of fitness, it leaves manager Roy Hodgson with problems ahead of the most taxing of England's three remaining games.
England started a game with Gerrard, Frank Lampard and Jack Wilshere together in midfield for the first time, while the injury blight meant Southampton striker Lambert was given his full debut as a lone striker. The 31-year-old had scored with his first touch in international football in last month's 3-2 friendly win over Scotland, but he spurned an early chance at a two-thirds-full Wembley, thrashing a half-volley wide.
It only took until the 12th minute for England to make the breakthrough, however. After an incursion down the left, Welbeck cut the ball back for Lampard and he in turn teed up Gerrard for the skipper to plant a beautifully struck shot in the bottom-left corner from 25 yards.
Stanislav Namasco prevented Jack Wilshere from adding a second by parrying from the Arsenal man, who had slalomed past Victor Golovatenco, but the Moldova goalkeeper was rather more generous in the 26th minute.
It could not have been a more straightforward first half, but Hodgson was left fuming after Welbeck picked up a yellow card, for shooting after the whistle had gone for offside, that rules him out of Tuesday's game.
He had the good grace to put it to the back of his mind immediately, though, brilliantly gathering Lambert's lofted pass, deftly eluding Namasco, and tucking in England's third in first-half injury time.
Five minutes into the second half, the same combination produced a fourth goal, with Welbeck running onto Lambert's slide-rule pass and calmly dinking the ball over the exposed Namasco with his left foot.
The contest over, Hodgson handed a debut to teenage Everton midfielder Ross Barkley, who replaced Wilshere with half an hour to play.
The 19-year-old almost marked his debut with a goal, drilling wide from outside the box in the 75th minute, and despite late attempts by Welbeck, Lampard, Kyle Walker and substitute James Milner, a fifth goal would not come.