Stuart Hogg will start the match at stand-off in place of Finn Russell who has been ruled out with a head knock.
The Scotland captain played the last 20 minutes of the defeat against Ireland last Sunday in the fly-half role.
He is partnered at half-back by Scott Steele who comes into the side for his first Scotland start. Regular scrum-half Ali Price is named among the replacements.
Hogg's switch to 10 means Sean Maitland goes to full-back, with Darcy Graham taking Maitland's wing berth.
There is also a change at outside centre, with Huw Jones preferred to Chris Harris. Jones scored a try as a second-half substitute in the 27-24 loss to the Irish.
In the forwards, there is a new second-row pairing with Sam Skinner and Grant Gilchrist replacing the injured Scott Cummings and Jonny Gray.
There are also two changes in the front row. Hooker David Cherry will make his first start for Scotland, with George Turner dropping to the bench.
Zander Fagerson is back at tighthead prop after serving his suspension following his red card against Wales. WP Nel drops out of the squad.
The Scotland v Italy match kicks off at 2.15pm, and is live on BBC1.