The duo are amongst 11 Warriors selected by Head Coach Gregor Townsend for this weekend's match in Santiago del Estro.
For Smith, a first cap for Scotland represents the latest landmark in a breakthrough season that saw him take home the club's Young Player of the Season award in addition to signing a new long-term deal to stay at Scotstoun.
Fagerson brings up his half-century of appearances six years on from his Scotland debut against England at BT Murrayfield, having played in each of his country's 11 Tests since returning from the 2021 British and Irish Lions tour to South Africa.
Scott Cummings comes into the starting XV for the first time this series, having impressed on his return from injury for Scotland A in their win over Chile at the start of the tour.
Rory Darge continues at blindside following a sterling shift in Salta last time out, after making 15 tackles in the 29-6 victory - more than any other Scottish player.
Another standout from Salta is retained at the base of the scrum, with Matt Fagerson having scored his first international try in last weekend's victory.
Ali Price is recalled to the starting lineup after coming off the bench last weekend, the scrum-half having also been named vice-captain by Townsend and the coaching team.
Sione Tuipulotu is called into the midfield to start at inside centre after missing out last weekend, as he makes his eighth appearance in the dark blue jersey.
Rufus McLean makes it eight Warriors selected to start, as the winger looks to build on his try-scoring showing in the win over Chile in Santiago.
Another of the try-scorers in Santiago is named amongst the replacements, with George Horne in line to win his first Scotland cap since November's defeat to South Africa at BT Murrayfield.
Ross Thompson continues in the number 22 jersey, having showcased his skills and contributed a brace of conversions after coming on at fly-half last weekend.
The Glasgow contingent is completed by Sam Johnson, as the centre rotates to the bench after scoring one of his country's four tries in Salta.
1 Rory Sutherland (Worcester Warriors)
2 Ewan Ashman (Sale Sharks)
3 Zander Fagerson (Glasgow Warriors)
4 Scott Cummings (Glasgow Warriors)
5 Jonny Gray (Exeter Chiefs) (Vice-Captain)
6 Rory Darge (Glasgow Warriors)
7 Hamish Watson (Edinburgh Rugby) (Captain)
8 Matt Fagerson (Glasgow Warriors)
16 Dave Cherry (Edinburgh Rugby)
17 Pierre Schoeman (Edinburgh Rugby)
18 Javan Sebastian (Scarlets)
19 Glen Young (Edinburgh Rugby)
20 Andy Christie (Saracens)
21 George Horne (Glasgow Warriors)
22 Ross Thompson (Glasgow Warriors)
23 Sam Johnson (Glasgow Warriors)