The hosts dominated throughout the contest and deservedly took the lead on 27 minutes when Lewis Price's rushed clearance ricocheted back off Bayern frontman Mandzukic, allowing him a simple tap-in.
Eduardo then poached a second just before the hour mark as Croatia laid down a marker of their credentials in the group.
Igor Stimac's side went into the contest boasting a formidable record on home turf and they took control from the kick-off.
First Ivan Rakitic saw a goalbound shot blocked and Eduardo had a low drive from distance well saved by the impressive Price before Gareth Bale gave Wales some respite with a long range drive on 20 minutes.
Milan Badelj then thumped in a volley that was beaten away by Price before Wales contributed to their own downfall just prior to the half-hour mark.
Ashley Williams put Price under pressure with a poor back pass, allowing Mandzukic to close him down, block his clearance and steer the ball into an empty net.
Croatia then contrived to miss a whole host of chances to double their lead with Eduardo, Ivan Perisic and Rakitic all going close ahead of the interval.
Wales looked to regroup but the one-way traffic continued after the break and Eduardo finally got his goal on 58 minutes when he pounced in the six-yard box after Price had somehow kept out Perisic's thumping header.
The visitors then survived an almighty goalmouth scramble and Luka Modric fizzed a superb effort just wide as the home team looked to notch up a cricket score.
However, with the points in the bag, Croatia appeared to take their foot off the gas and Andy King could so easily have reduced the arrears when he planted a header straight at Stipe Pletikosa from Joe Allen's pinpoint cross.
Indeed, Wales pushed in the final quarter of the contest and Bale, the two-goal hero of Saturday's win over Scotland, twice showed just why his regarded as one of the biggest talents on the planet.
First he embarked upon a 30-yard run that took him beyond three defenders before drilling in a shot that was beaten away by Pletikosa, with substitute Sam Vokes blazing the rebound over.
And he came close again in the dying seconds with a 25-yard free-kick - but it was not enough to halt Croatia's march towards Brazil, or prevent Wales from remaining second-bottom in Group A.
BELGIUM 2-0 SCOTLAND
Belgium demonstrated a gulf in class over Scotland with a 2-0 victory on Tuesday that maintained their lead at the top of World Cup qualifying group A.
Christian Benteke headed the opener from a Kevin De Bruyne cross after 69 minutes and defender Vincent Kompany secured the points with a wonderful individual goal two minutes later.
Only several fine saves from Scottish keeper Allan McGregor, Belgian imprecision and some luck had kept Scotland in the game for more than an hour.
The visitors' two best chances came from free kicks on the edge of the Belgian penalty area. Shaun Maloney forced keeper Thibaut Courtois to leap high to his right in the 24th minute, while Kris Commons stretched Courtois shortly before halftime.
Belgium made their dominance pay after the break, first through Benteke's far-post header and then through Kompany, who turned neatly just inside the area before whipping a right-foot shot into the top right-hand corner of McGregor's goal.
Belgian have 10 points from four games and lead Croatia on goal difference, with the group increasingly looking like a battle between the two, particularly after Serbia's 1-0 defeat in Macedonia.
Scotland, who conceded two late goals in a 2-1 defeat to Wales on Friday, are bottom of the section with two points from four games.
MACEDONIA 1-0 SERBIA
Serbia's hopes of reaching their second successive World Cup as an independent nation took a serious blow after they slipped to a 1-0 defeat at southern neighbours Macedonia after a lacklustre performance in Skopje on Tuesday.
The loss left the Serbians with four points from as many games, six behind Belgium and bitter regional rivals Croatia, whom they visit in a potentially explosive clash in March.
Serbia coach Sinisa Mihajlovic surprisingly left captain Branislav Ivanovic on the bench and the decision backfired spectacularly as his replacement Nenad Tomovic was sent off in the 58th minute.
The right back hauled down Macedonia striker Ferhan Hasani and the live wire Agim Ibraimi, who supplied the defence-splitting pass that left Tomovic stranded, steered in the penalty to the delight of the vociferous home fans.
Hasani and Ibraimi gave the Serbian defence a roasting after a tepid first half in which neither side created a clear cut chance while both gave away possession in midfield time and again.
Dusan Tadic nearly snatched an equaliser when he shot wide after a good solo run and winger Zoran Tosic skied his shot from 12 metres over the bar with time running out.