Kinghorn gets the nod ahead of uncapped Ireland-born number 10 Ben Healy (23) as Townsend fills the gap left by the injured Finn Russell (30). Healy is on the bench.
Smith is in the side for regular full back Stuart Hogg (30), who has an ankle problem.
Sam Skinner (28) comes into the second row in the place of the injured Richie Gray (33), while Hamish Watson (31) returns at flanker in the final change following the 22-7 home loss to Ireland last weekend.
"Blair has been doing well off the bench and Ollie played very well for us against Australia last November and has carried on with that form," Townsend said.
"Sam has been unlucky to miss out with the quality of second rows we have. Along with Hamish, both are experienced players, fresh and motivated for this weekend."
Former Ireland junior international Healy is a player Townsend is eager to see in action.
"He has been outstanding and very good in terms of what we want. He has taken things on board, is a very skilful player and has a very good kicking game. He is knowledgeable about when to attack."
Townsend says they are taking nothing for granted against an Italian side that is winless in this year’s championship, but have played some excellent rugby.
"We are determined to win, but Italy will test us, they are playing outstanding attacking rugby. They will ask us questions and play with passion," Townsend said.
Scotland are out of the running for the Six Nations title, but could finish as high as second in the table.
