He has captained the Scotland Under-21s but will be leading the A side for the first time.
Macfadyen, 27, said: "This is a massive honour for me. Monday will be a big challenge and I'm really looking forward to it."
Only full-back Rory Lamont, winger Simon Webster, lock Andy Hall and number eight Johnnie Beattie retain their places after Scotland's tough 13-9 win over the USA on Wednesday.
With Gordon Ross out of the tournament with a broken bone in his hand, Phil Godman starts at fly-half, with Wasps' Heineken Cup winner Mark McMillan coming in at scrum-half.
Simon Danielli replaces Thom Evans on the wing while Nick de Luca and Robbie Kydd form a new centre partnership.
Up front, Craig Smith, Fergus Thomson and Ed Kalman form a new front row, Bourgoin's Mark Rennie comes in at lock and Alasdair Strokosch joins Beattie and Macfadyen in the back row.
England Saxons head coach Jim Mallinder has named four of Wasps' European Cup winners in his side.
Dan Cipriani, who started at full-back in Wasps' 25-9 victory over Leicester last Sunday, comes in for Ryan Lamb at fly-half while Tom Voyce and Paul Sackey fill the wing positions and James Haskell slots in as blindside flanker.
Mallinder has also included Olly Barkley and Nick Abendanon, who missed last weekend's 51-3 victory over the USA to play for Bath in the European Challenge Cup final against Clermont Auvergne.
"I'm very excited at the thought of seeing Abendanon, Sackey and Voyce playing together. They all played very well in European competitions last weekend," said Mallinder.
The Saxons are without inside centre Shane Geraghty, who damaged a hamstring against the USA, while winger Dan Scarbrough was called into the senior England squad in South Africa during the week.
Five of the Saxons' changes come in the backs, while Haskell's inclusion sees Newcastle loose-forward Phil Dowson switch to number eight and Jordan Crane moved to the bench.
The Saxons will again be captained by London Irish prop Neal Hatley.