Fresh from their dramatic last-gasp win in Twickenham, the Wallabies raced out of the blocks at Principality Stadium, racing into a 19-0 lead.
Wales got back to within six points by half-time, but even after Samu Kerevi was shown a red card on the occasion of his 50th cap, it was Australia who pulled clear once again as Matt Faessler and Tom Wright both scored hat-tricks.
With this win, Australia are now halfway to completing their Grand Slam ambition, with trips to Edinburgh and Dublin still to come, while Wales have now lost 11 in a row ahead of the visit of South Africa next weekend.
Australia showed their intent from the off setting up camp in the Wales half from kick-off. Their first real chance came when the elusive Wright got away down the left, combining with Max Jorgensen, who in turn found Kerevi.
The centre was somehow hauled down by winger Tom Rogers, who was able to hold him up over the line and prevent the try.
But it did not take long for them to strike, Wright bouncing off a tackle from Blair Murray before racing over from the 22.
That was followed by a score from even further out by second row Nick Frost. Taking advantage of a lost ball just inside Australian territory, the lock showed his athleticism to race more than 50 metres for the try. Noah Lolesio converted and suddenly Australia were 12-0 up.
Midway through the half they had another, Faessler getting the first of his hat-trick of tries from a rolling maul, showing his strength after they had initially been stopped.
At 19-0, Wales looked shellshocked but they battled back well before half-time. With a powerful scrum, they were able to put pressure on the Wallabies and Aaron Wainwright ran a beautiful arcing line to crash over next to the posts.
Gareth Anscombe converted and added two more penalties to cut the deficit to six at half-time.
Australia’s cause was not helped immediately after half-time when Kerevi tackled Jac Morgan high and was shown a yellow card which was then upgraded to a 20-minute red card.
Despite being down a man, it was the Wallabies who effectively made the game safe over the next 20 minutes, scoring three more tries.
Faessler grabbed two in five minutes, both from driving mauls, on his way to becoming the first Australian hooker to score a Test hat-trick.
Trailing 33-13, Wales thought they had a try back when James Botham did brilliantly to pick up a loose pass and get over in the corner. Unfortunately for him, the pass to him was forward and the try was ruled out.
Any hopes of a comeback were extinguished when Wright picked off a pass and raced home from halfway, Lolesio bringing up 40 points with the conversion.
Wales did come back and get their second try of the afternoon, Ben Thomas finishing after a deft pass from Botham.
Australia responded immediately however, Len Ikitau standing up Cam Winnett to run in their seventh try.
There was still time for one more, Tate McDermott slipping out of a number of tackles before putting Wright away for his hat-trick.
