Stewart will resume her international career on the wing at Accor Stadium on Saturday after overcoming an Achilles injury, while Karpani and Smith join Allana Sikimeti and Piper Simons as the new faces on the bench.
Karpani is closing in on 50 Test matches for the Wallaroos, playing her 49th this weekend before a possible half-century in Canberra next Friday.
Desiree Miller will start at fullback with Caitlyn Halse ruled out with concussion symptoms.
Miller's move to No.15 shifts Amelia Whitaker to the left edge, with Stewart making up the backline on the right.
Wallaroos captain Siokapesi Palu Sekona and Pia Tapsell switch roles in the back row.
"We have maintained considerable selection consistency throughout the WXV, strategically strengthening our cohesion and combinations," high performance director Tim Walsh said on Thursday.
"During the WXV we have layered specific areas of our game to build stronger performances each Test.
"We have selected a balanced 23 armed with leadership, power, strength and speed."
The Wallaroos will kick off a massive quadruple header at midday, to be followed by the Australia sevens sides taking on Fiji and New Zealand, while the Wallabies host the All Blacks at 3.45pm (AEDT).
The Wallaroos have played Scotland on five occasions for five wins, including last month's WXV Global Series fixture in Edinburgh.
This is the first time the Scots are touring Australian shores, with the final Test match of the season wrapping up next week at GIO Stadium.
WALLAROOS SQUAD: Brianna Hoy, Brittany Merlo, Faliki Pohiva, Kaitlan Leaney, Michaela Leonard, Siokapesi Palu Sekona (capt), Piper Duck, Pia Tapsell, Samantha Wood, Waiaria Ellis, Amelia Whitaker, Faitala Moleka, Georgina Friedrichs, Maya Stewart, Desiree Miller. Reserves: Tania Naden, Allana Sikimeti, Eva Karpani, Jemma Bemrose, Emily Chancellor, Lily Bone, Piper Simons, Cecilia Smith.
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