Both men missed last weekend's narrow win at the Waratahs as their side secured a place in the knockout stages. Horwill and Genia were unsurprisingly rested for that 14-12 victory in Sydney following the crushing nature of their third Test defeat to the Lions in the same city on July 6.
Horwill played the full 80 minutes in all three internationals against Britain and Ireland's elite, while Genia did the same in Brisbane and Melbourne before being replaced when the result of the final encounter was beyond doubt.
Reds director of coaching Ewen McKenzie, who has just been named the new Wallabies boss once the domestic season finishes, will be hoping that the influential duo return refreshed and refocused as his team look to upset the odds against the most successful side in the history of Super Rugby.
The Reds haven't won in Christchurch since 1999, although they have only played in the city once under McKenzie's stewardship when they lost 15-11 loss last year. The Queensland-based franchise have recent form in their favour, though, having won three of their past four encounters with the Crusaders, including the Super XV title-winning triumph of 2011 at the Suncorp Stadium.
They will have to repeat that feat without wing Rod Davies and utility back Mike Harris due to knee and hamstring injuries respectively, while centre Anthony Faingaa doesn't make the matchday squad having been unable to train earlier in the week because of his own hamstring problems.
"There is always going to be some damage at this time of the year and, while it's disappointing to be without a few guys, we are getting the experience of James and Will back," said McKenzie, after naming Jono Lance at inside centre and Dom Shipperley and Chris Feauai-Sautia on the wings.
"Their influence can't be understated and you need world-class players and strong leaders if you are going to win these games on the big stage.
"We have had to reshuffle our backline in some positions and the players coming in now have an opportunity to contribute in a positive way. They've all had plenty of experience this year in the roles we are asking of them and we've got every confidence in our entire squad to get the job done.
"History tells us the Crusaders have a strong record at home where they seemingly always find a way to prevail, but we pushed them in Christchurch in our last match and many teams have continued to do so and come close since.
"It's a challenge we look forward to and the Crusaders are always a match we enjoy playing. We take pride in the hoodoos we've broken over the years and this is just another milestone we can target. Traditionally, this Reds group has also stepped up and performed well in the big games, and that gives us confidence in tackling the opportunity we have in front of us on Saturday."
Reds (vs Crusaders, Christchurch 8.35am BST)
Ben Lucas; Dom Shipperley, Ben Tapuai, Jono Lance, Chris Feauai-Sautia, Quade Cooper, Will Genia; Greg Holmes, Saia Faingaa, James Slipper, Rob Simmons, James Horwill (c), Eddie Quirk, Liam Gill, Jake Schatz
Replacements: Albert Anae, Jono Owen, Ed O'Donoghue, Radike Samo, Beau Robinson, Nick Frisby, Luke Morahan