Danny Wilson’s side have a quarter-final spot in the bag following last week’s stunning defeat over Toulouse at Cardiff Arms Park, which took them to four wins in five games in the competition.
The reverse fixture at Cardiff Arms Park earlier in the season saw the Blues claim a bonus point 29-19 victory over Lyon, who were TOP14 leaders in the early stages of the season.
Wales' Capital Region must wait to find out their quarter-final opponents, with trips to Edinburgh and Connacht amongst the possibilities.
Wilson has made six changes from the side that beat Toulouse, with Macauley Cook recalled into the back row, alongside Josh Navidi and Ellis Jenkins.
The utility forward crossed the whitewash against Lyon in October, before scoring the winning try against Toulouse at Stade Ernest Wallon a week later.
Elsewhere in the pack, Dillon Lewis, who was named in Wales' NatWest Six Nations squad earlier in the week, comes in at tighthead, while Damian Welch is added to the second row.
Rey Lee-Lo, Lloyd Williams and Blaine Scully are the changes made to the backline.
On the bench, Olly Robinson, Rhun Williams, Kirby Myhill, Scott Andrews and James Down all return to the matchday squad.
Lyon have included experienced French international half-back partnership, Frederik Michalak and Lionel Beauxis, in their line-up, with former England and Toulon back, Delon Armitage, named on the wing.
What They Said
Wilson is delighted with his side's achievements in the Challenge Cup this season, and insists a win on Saturday will boost momentum ahead of a return to PRO14 action when the Blues host Cheetahs on February 10.
"Ultimately we're going to Lyon to win. We certainly don't want to finish with a loss in this group, which we've performed very well in," said Wilson.
"As a group, we know how important momentum is and I'm confident we'll pick a team who are confident and will approach the game with the relevant manner to get an away win.
"We beat Lyon at home, we beat Toulouse home and away and if we can get another French scalp it will be a big achievement. The important thing for us is to keep rolling with the momentum.
"We've done what we can do in qualifying for the quarter finals. We can't influence whether we get a home tie and the odds are very highly stacked against us to get that.
"We were obviously really pleased with the end result of qualifying for the quarter final and winning our group with a game to go.
"If you had said that to me when the group was announced I certainly would've taken it. Toulouse and Sale were both in the Champions Cup the season before and Lyon are going extremely well in the league and are heavyweights in France in terms of budget.
"To come out of that group, winning it with a game to spare, is a great achievement.
Following a call-up to Warren Gatland's Wales squad earlier in the week, Ellis Jenkins insists his focus rests solely with Cardiff Blues and their final match in the group stages of the European Challenge Cup.
He said: "That's why you play and train so hard to play rugby, you want to compete at the highest level and compete for honours.
"To give ourselves a chance of progressing now through the knockout stages is something we're definitely proud of but we know it's knockout rugby now and will be a big challenge.
"The other groups have gone against us really with regards to the away quarter-final but we approach it (Lyon) as you would with any game. You are going there to win, to put in a performance and it's an opportunity for us to give people a little bit of a rest, other people game time where they haven't played so much, myself included.
"It's also an opportunity for us to try a few things that we have been thinking of bringing in but the games were too important to try things, we can experiment a little bit.
"We're not sure what Lyon will bring because they are out of the competition. We're not sure if they will put a weakened team out or try to get a bit of a running start into the league.
"It will be a different game out there. We have to go there and front up because at home they will be extremely proud and the surface could be a little bit different.
"But we're in a good place from our last couple of performances and just have to carry that on."