The Edinburgh midfielder was due to start in Dublin last weekend but was forced to withdraw at the last minute after aggravating a previous injury in the warm up.
De Luca replaces clubmate Lee Jones in the starting side after the newcomer suffered concussion at the Aviva Stadium.
Max Evans moves from centre to wing to accommodate De Luca and cover for Jones but head coach Andy Robinson has opted against further alterations to his first XV despite the 32-14 scoreline last time out.
Bath back-three player Jack Cuthbert is the only change on the bench as he takes the place of Matt Scott who made his debut on Saturday in De Luca's absence.
"Nick was unfortunate to miss the game in Ireland through a hamstring problem and the challenge for him on Saturday will be to contribute as purposefully against the Italians as he did in his last game, against France," said Robinson.
"Jack has featured regularly for Bath this season. He's strong and we know from his involvement with the squad back in the summer how much it means to him to play for Scotland.
"We are not where we wanted to be at this point in the championship. Yes, we have played some good rugby at some points in games and there has been some improvement but we all know that we need the substance that comes from a win, especially after the display in Dublin."
Scotland have now lost six games in a row and know defeat in Rome will condemn them to the Wooden Spoon and their worst run of results since 1998.
The Scots are without a victory in the Italian capital since 2006 but Robinson has shown faith in his team to turn things around.
Scotland (v Italy, Rome, Saturday, 12.30pm GMT)
15 Stuart Hogg (Glasgow Warriors)
14 Max Evans (Castres)
13 Nick De Luca (Edinburgh Rugby)
12 Graeme Morrison (Glasgow Warriors)
11 Sean Lamont (Scarlets)
10 Greig Laidlaw (Edinburgh Rugby)
9 Mike Blair (Edinburgh Rugby)
1 Allan Jacobsen (Edinburgh Rugby)
2 Ross Ford (captain, Edinburgh Rugby)
3 Geoff Cross (Edinburgh Rugby)
4 Richie Gray (Glasgow Warriors)
5 Jim Hamilton (Gloucester)
6 John Barclay (Glasgow Warriors)
7 Ross Rennie (Edinburgh Rugby)
8 David Denton (Edinburgh Rugby)
16 Scott Lawson (Gloucester)
17 Euan Murray (Newcastle Falcons)
18 Alastair Kellock (Glasgow Warriors)
19 Richie Vernon (Sale Sharks)
20 Chris Cusiter (Glasgow Warriors)
21 Ruaridh Jackson (Glasgow Warriors)
22 Jack Cuthbert (Bath Rugby)
NB Bold denotes Lion