Wales’ Capital Region booked their place in the quarter-finals with a second victory over Toulouse last weekend.
They had slim hopes of a home quarter-final but were determined to finish the group stages on a high against the French giants, who were at full-strength.
It took the home side just 24 seconds to claim the opening try but Danny Wilson’s men were to be undeterred.
They trailed 12-0 following a second Lyon try but Lloyd Williams struck with the final play of the first-half to stay in touch.
A penalty try early in the second-half momentarily put them in front and they continued battling with replacement scrum-half Tomos Williams sealing the win.
The Blues made a nightmare start to the encounter as Lyon claimed the opening try after just 24 seconds.
Jarrod Evans got the match underway but his side were caught napping as they missed a succession of first up tackles as Lyon went the length with Jone Tuva making good yards and Dylan Cretin finishing.
Beauxis converted the effort to give his side an early 7-0 lead at the Matmut Stadium. The Blues regained their composure and came very close to replying almost instantaneously.
A chip over the top unlocked the Lyon defence and with Lloyd Williams and Blaine Scully winning the race to the ball a try appeared certain but on the greasy surface and with a tricky bounce, the USA captain knocked on.
The frenetic nature of the game continued with a Beauxis cross-kick almost putting Tuva away but he was unable to collect in the in goal area.
Cardiff Blues dominated much of the first half in terms of both territory and possession but the final pass wasn’t quite sticking as Lyon clung on.
Several opportunities went begging as the Blues kicked to the corner but were unable to turn pressure into points.
And they were dealt a major blow on 24 minutes when the home side demonstrated their clinical edge with a second try.
It had been all Cardiff Blues but when the ball was lost at a lineout, Lyon surged through the middle. Prop forward Stephane Clement found himself in unusual space and rampaged forward.
Anscombe made the crucial tackle but the hosts displayed great speed of thought as they chipped from the breakdown to the corner and Cuthbert was unable to collect under pressure from Tuva, with Pierre-Louis Marassi pouncing on the loose ball.
Beauxis failed to land the tricky conversion but his side were now in command with a 12-0 lead.
Wales Capital Region continued to enjoy plenty of opportunity and they would perhaps be aggrieved that referee Matt Carley did not further punish Lyon for a succession of infringements in the redzone.
Following a sustained period of pressure Williams, Welch and Rey Lee-Lo all went close but just when it appeared that slick hands from Dillon Lewis and Ellis Jenkins had released Welch, Tuva stripped the ball and Lyon survived.
The Blues were let off the hook on 33 minutes as Anscombe’s grubber through rebounded and Lyon surged forward but the ball was knocked on.
But thankfully following 40 minutes of endeavour, but no end product, the Blues struck with a stunning try.
Jarrod Evans dummied his way through the Lyon defence in trademark fashion and with support on either side, he passed to scrum-half Williams on his inside, who showed great pace and power to fend two defenders and score under the posts.
Evans slotted the conversion to bring the Blues within five points at the interval.
Despite a bright start to the second-half from the hosts, the Blues soon took the lead. A big hit in midfield from Lee-Lo lifted his side and minutes later they were in front.
Evans kicked a penalty to the corner and after Welch won the ball and his pack surged forward with Lyon infringing again, Carley ran out of patience and awarded the penalty try.
The partisan home crowd were not happy but after committing the same offence on several occasions in the first half, they could have few complaints.
Just when momentum was beginning to turn, the gargantuan French pack flexed their muscle with a driving lineout, which surged forward at a rate of knots.
It was pulled down and despite Freddie Michalak wanting a quick-tap he was hauled back as Evans was shown yellow.
Lyon’s numerical advantage did not last long as Barassi joined Evans in the sin-bin for taking out Cuthbert in the air, however a pair of Beauxis penalties edged them into a 18-14 lead.
The introduction of Tomos Williams proved a turning point as he had three decisive touches in the space of two minutes.
First he broke from inside his own 22 and found Scully in support. The wing did remarkably well to hold onto the ambitious pass and when Carley awarded a penalty at the breakdown, Williams maintained the tempo with a quick-tap.
He was tackled short by Jean Marcellin Buttin as the support failed to keep up with the livewire replacement but when play went to the right touch line and back to the right he was on hand to finish following another fine Evans break.
Lyon hammered away at the Blues for the final 10 minutes and were camped on the try-line with a succession of driving line outs and five-metre scrums as the clock passed 75 minutes. But Cardiff Blues defended superbly to hang on for a deserved victory, which secured a second double over French opposition.