Melbourne Rebels back Reece Hodge will make his first start of this season, with five changes flagged to the side's starting XV to face the Lions.
Hodge, who has made two appearances off the bench in 2019, will start in the number 11 jersey, replacing Marika Koroibete on the wing.
Joining the star Wallaby in the starting XV is prop Tetera Faulkner, hooker Anaru Rangi, flanker Luke Jones and lock Ross Haylett-Petty, who will also start for the first time this season.
The changes to the side mean Matt Gibbon, Robbie Abel, Matt Philip and Koroibete will join the match from the bench, while flanker Rob Leota has been omitted from this week's side.
Home-grown talent Sione Tuipulotu has been named as a replacement centre, in what could potentially be the 22-year-old's first game for Melbourne since 2017.
Melbourne Rebels Head Coach Dave Wessels says the decision to move Koroibete to the reserves was motivated by Hodge's kicking ability, while also keeping the Wallaby winger fresh ahead of a tough run of six consecutive fixtures.
"I thought Marika played really well against the Brumbies," Wessels said.
"However, we’ve got a run of eight games and we are just trying to be smart about whoever’s taking to the field is fresh and I think Hodgey brings a kicking game at altitude which could be valuable for us."
The Melburnians will be out to create history and claim a historical first win in South Africa this Saturday.
And the Head Coach believes this is the best chance the Rebels have had in achieving the feat, saying the playing group's drive to continually better themselves will help propel the side to a strong performance.
"We are a different team to Rebels teams that have come here in the past," Wessels said.
"Right from the start of the season, our focus has been on trying to find the best version of ourselves and that’s got us to where we are now."
In the lead up to the Round 5 clash, Wessels has revelled in being back in his home nation of South Africa.
Wessels has also experienced a sentimental preparation for the Lions fixture, with the Head Coach having previously been a former pupil of the Rebels' Johannesburg training base at St Stithians College.
"I went to school there, my brother went there, my sister went there, so we’ve had a long association with the school, so it was cool to be back there," he said.
"I played in the mighty third team there. When I was there, I never actually played on the main field because it was reserved for the first team, so it was funny to go back and train on the main field because I was never allowed on it."
Melbourne Rebels match day 23 v Lions at Emirates Stadium, Saturday, kick off 3:05pm (12:05am Sunday EDT)
1. Tetera Faulkner
2. Anaru Rangi
3. Sam Talakai
4. Ross Haylett-Petty
5. Adam Coleman
6. Luke Jones
7. Brad Wilkin
8. Isi Naisarani
9. Will Genia
10. Quade Cooper
11. Reece Hodge
12. Billy Meakes
13. Tom English
14. Jack Maddocks
15. Dane Haylett-Petty
16. Robbie Abel
17. Matt Gibbon
18. Jermaine Ainsley
19. Matt Philip
20. Angus Cottrell
21. Michael Ruru
22. Sione Tuipulotu
23. Marika Koroibete