Tuipulotu is expected to miss the entire competition in a huge blow for coach Gregor Townsend, but McDowall will be able to show his quality as he partners Huw Jones in the midfield.
Blair Kinghorn is at fullback, with Duhan van der Merwe and Darcy Graham on the wings. Co-captain Finn Russell is at flyhalf with Ben White making up the halfback pairing.
Matt Fagerson is at number eight, with flankers Rory Darge (also co-captain) and Jamie Ritchie in the back row, while Jonny Gray and Grant Gilchrist make up the lock pairing.
Hooker Dave Cherry has props Pierre Schoeman and Zander Fagerson either side of him. Cherry will play his first game since the 2023 Rugby World Cup.
"They bring experience and a real motivation to play well. The Scotland jersey brings that out in you," Townsend said of the pair.
Scotland are seeking to lift the trophy for the first time since 1999, the last year it was known as the Five Nations and before Italy's entry into the competition.
"Getting to start at home is massive and it has been a good training week. Italy are a quality side and have shown that for two or three years," Townsend said.
"They have been a difficult opponent for us and other teams. They really upped their game in last year's Six Nations with two wins and a draw, and one of those victories was against us, so they will be confident.
"There is intelligence in how they play, when they look after the ball, when they move it. They are a quality side and play with a lot of passion."
Scotland XV: 15-Blair Kinghorn, 14-Darcy Graham, 13-Huw Jones, 12-Stafford McDowall, 11-Duhan van der Merwe, 10-Finn Russell (co-captain), 9-Ben White, 8-Matt Fagerson, 7-Rory Darge (co-captain), 6-Jamie Ritchie, 5-Grant Gilchrist, 4-Jonny Gray, 3-Zander Fagerson, 2-Dave Cherry, 1-Pierre Schoeman
Replacements: 16-Ewan Ashman, 17-Rory Sutherland, 18-Will Hurd, 19-Gregor Brown, 20-Jack Dempsey, 21-George Horne, 22-Tom Jordan, 23-Kyle Rowe.
