Wales’ Capital Region made an encouraging start in Swansea and led 10-3 after 15 minutes thanks to a Kristian Dacey try and the boot of Gareth Anscombe.
But the sin-binning of Dan Fish proved a turning point and the hosts racked up 19-points during the yellow card period. Alun Wyn Jones crossed and Eli Walker claimed a brace to open up a 12-point lead and Danny Wilson’s side never recovered.
Dimitri Arhip, Ben John and Dan Evans also claimed tries as the Ospreys dominated on home soil.
Tom James snatched a score against the run of play before Josh Matavesi responded. Rey Lee-Lo had the final word but it was too little, too late on a forgettable night.
Cardiff Blues made an assured start at the Liberty Stadium and controlled territory in the opening five minutes.
An early penalty was kicked to the corner and the visitors went through the phases before the ball was turned over.
With a miss-match and an overlap, the Ospreys went on the counterattack from inside their own 22. Rhys Webb and Justin Tipuric looked to combine but Kristian Dacey and Anscombe did superbly well to scramble across and the hosts lost the ball.
The Blues continued in the ascendant and Anscombe opened the scoring on 10 minutes following a ruck penalty.
However they failed to exit from the restart and conceded a soft penalty which allowed Sam Davies to level the scores.
The Blues were soon awarded a penalty of their own, just outside Anscombe’s range, which was knocked to the corner.
Josh Turnbull took the line-out and a slick driving maul was set-up. It rumbled over with ease, allowing Dacey to touchdown in the corner and Anscombe curled his conversion through the posts for a 10-3 lead.
However Wales’ Capital Region were dealt a major blow shortly after the quarter-mark and the Ospreys drew level once again.
Dan Fish’s clearance was charged down by Davies, who collected the ball. Fish recovered but tackled Davies without the ball and was subsequently sent to the sin-bin with the Ospreys awarded a penalty.
They too went to the corner and former BT Sport Cardiff Arms Park favourite Bradley Davies took the line-out but the Blues defended superbly.
The Blues drove the Ospreys backwards but following a succession of phases Alun Wyn Jones snuck through the breakdown to stretch over.
Minutes later the Ospreys were presented with another kickable penalty which Davies dinked into the corner.
Once again the Blues pack held firm and forced a turnover to allow Lloyd Williams to clear but the relentless Ospreys were quickly back on the attack.
They were stretching the Cardiff Blues’ 14 man defence before Davies delayed a short pass to Walker, who eased around Garyn Smith to race over.
Davies was unable to add the extras but the try had given the hosts a five-point lead, the first time they were in front in the encounter.
Two minutes later the Ospreys claimed a third quick-fire try while Fish was in the sin-bin.
Dan Evans launched a counter-attack, taking full advantage of several teammates in front. He was hauled down short but the damage was done and following some quick snipes around the fringes, Walker was released to squeeze in the corner unopposed.
Davies converted from the touchline to leave the Blues trailing 22-10. Wilson’s men rallied and went on the attack to claw back some valuable points but matters went from bad to worse when the Ospreys turned over possession close to their own line.
Matavesi tore into the Blues half before he was finally brought down by Anscombe, but the Swansea-based region maintained possession and claimed a bonus-point try through Dimitri Arhip. Davies could not add the conversion but the try left the Blues staring down the barrel, trailing 27-10.
Wilson made a host of changes at half-time, bringing James Down, Steve Shingler and Matthew Morgan on for Josh Navidi, Garyn Smith and Dan Fish.
But the Blues got off to the worst possible start as they failed to secure the restart and Ben John scored within 22 seconds.
The hosts added a sixth try on 46 minutes, with Evans finishing an Ashley Beck break. Tom James scooped up some loose ball to race clear for his fourth try of the season, but the hosts continued to control affairs and Matavesi scored his side’s seventh.
Rey Lee-Lo finished superbly in the closing stages after Blaine Scully tapped back a Anscombe cross-kick, with the fly-half converting.