Leinster's Rhys Ruddock will make his first start for Ireland, winning his third cap in a back row that contains Chris Henry and Jamie Heaslip who returns at number 8.
Devin Toner also comes back into the starting line-up, rejoining captain Paul O'Connell in the second row. O'Connell's Munster colleague Dave Kilcoyne is set for his second start in 10 Tests in the front row.
Rob Kearney replaces Felix Jones at full-back with both wingers Andrew Trimble and Simon Zebo retained from the opening Test win last weekend.
Fergus McFadden is promoted from the bench to wear the number 13 jersey with Darren Cave switching to inside centre. It will be McFadden's first start at outside centre since the 2012 Six Nations game against Wales.
Eoin Reddan comes in at scrum half some seven years on from his first start in green during the 2007 summer tour to Argentina.
There are three uncapped players on the replacements bench - Ulster hooker Rob Herring, Munster prop James Cronin and Leinster's Noel Reid.
Commenting on the team selection, head coach Joe Schmidt said: "We brought 29 players away on tour and we wanted to make sure we recognised the amount of effort that they made on the training pitch and to be well prepared to train well and they all have, so we wanted to give them an opportunity to demonstrate that in a Test match arena.
"We try to keep a little bit of a spine through the team. Damien Varley is one I would feel a little bit of sympathy for. I think he made a really good impact coming off the bench last weekend.
"I thought Robbie Diack played really and I thought Felix Jones was pretty much flawless at full-back, apart from one time when he knocked the ball back into the 22 and we put it out. But those guys unfortunately missed out to guys who add a little bit of freshness.
"Rob Kearney coming in for Felix, for example, he has got a lot of experience as well and we just feel there could be a bit of an Argentinian backlash, the fact that they will be wanting to make sure in what is the heart of rugby, a little bit, in Argentina and Tucumán."
Asked about the three potential debutants on the bench, he added: "I think it is a massive day for them. We have been massively impressed with how they have acquitted themselves in the training environment, in the way they have prepared themselves and made sure that the training changes are reasonably seamless.
"So, for James Cronin, I think his kind of whirlwind progression from just getting a start this year with Munster right through to potentially getting on in a Test match is fantastic for him.
"I don't think any of those three guys are the finished product but it will be another step towards giving them the confidence to continue to grow and hopefully add further value to us."
The second Test will take place at Estadio José Fierro in Tucumán and will be televised live on Sky Sports 2 HD (coverage begins at 7.30pm).
IRELAND Team & Replacements (v Argentina, Estadio José Fierro, Tucumán, Summer Tour, Saturday, June 14, kick-off 3.40pm local time/7.40pm Irish time):
15. Rob Kearney (UCD/Leinster) 54
14. Andrew Trimble (Ballymena/Ulster) 56
13. Fergus McFadden (Old Belvedere/Leinster) 27
12. Darren Cave (Belfast Harlequins/Ulster) 6
11. Simon Zebo (Cork Constitution/Munster) 7
10. Jonathan Sexton (Racing Metro 92) 44
9. Eoin Reddan (Lansdowne/Leinster) 54
1. Dave Kilcoyne (UL Bohemians/Munster) 9
2. Rory Best (Banbridge/Ulster) 76
3. Mike Ross (Clontarf/Leinster) 40
4. Devin Toner (Lansdowne/Leinster) 16
5. Paul O'Connell (Young Munster/Munster) 93 (capt)
6. Rhys Ruddock (St. Mary's College/Leinster) 2
7. Chris Henry (Malone/Ulster) 15
8. Jamie Heaslip (Dublin University/Leinster) 66
16. Rob Herring (Ballynahinch/Ulster) *
17. James Cronin (Dolphin/Munster) *
18. Jack McGrath (St. Mary's College/Leinster) 9
19. Iain Henderson (Ballynahinch/Ulster) 11
20. Jordi Murphy (Lansdowne/Leinster) 3
21. Conor Murray (Garryowen/Munster) 28
22. Ian Madigan (Blackrock College/Leinster) 9
23. Noel Reid (Clontarf/Leinster) *
* Denotes uncapped player