Weir, 21, who has won his three previous caps from the bench, is one of two changes to the starting lineup who defeated Ireland in the last round.
British and Irish Lions tighthead prop Euan Murray, who missed the Ireland match because he does not play on Sundays for religious reasons, replaces Geoff Cross who returns to the bench.
"It's a moment I'll cherish and hopefully I can do the coaches justice for giving me the start," said Weir.
Scotland interim head coach Scott Johnson said Weir had played well after coming on as a replacement in the 12-8 win over Ireland on Feb. 24.
"He's a talent with a really good work ethic and a thirst to improve, which I like a lot," Johnson said.
"Ruaridh remains a key part of our squad but he knows with Tom Heathcote proving a match-winner for Bath and kicking goals from here, there and everywhere, that he needs to up his game too.
"Geoff was a standout against Ireland and it's up to Euan, who fronted up big time against Italy, to raise the bar again."
Scotland, who have beaten Italy and Ireland after losing to England in the first round, share second place in the standings with Wales on four points. England, the only unbeaten team with two rounds remaining, head the table with six points.
Team: 15-Stuart Hogg, 14-Sean Maitland, 13-Sean Lamont, 12-Matt Scott, 11-Tim Visser, 10-Duncan Weir, 9-Greig Laidlaw, 8-Johnnie Beattie, 7-Kelly Brown (captain), 6-Robert Harley, 5-Jim Hamilton, 4-Richie Gray, 3-Euan Murray, 2-Ross Ford, 1-Ryan Grant.
Replacements: 16-Dougie Hall, 17-Moray Low, 18-Geoff Cross, 19-Alastair Kellock, 20-Ryan Wilson, 21-Henry Pyrgos, 22-Ruaridh Jackson, 23-Max Evans.
- Sports & Recreation
- Euan Murray
- Geoff Cross