Twelvetrees will become the 18th new player capped by head coach Stuart Lancaster in 13 Tests when he lines up alongside Brad Barritt in a rejigged England midfield for the RBS 6 Nations opener.
Barritt will revert to the outside centre role he filled on his own Test debut in last year's Calcutta Cup win at Murrayfield, with Twelvetrees operating on his inside.
Joe Marler has returned at loosehead prop in place of Alex Corbisiero, who has been ruled out of the Six Nations with a knee problem.
That means Tom Youngs keeps the hooker's jersey ahead of the more experienced Dylan Hartley, who missed the autumn series through injury.
Ben Youngs has held off the challenge from Danny Care to keep hold of the scrum-half position and Alex Goode returned from a shoulder injury in time to retain the full-back berth.
"We are happy to stick with the team that did so well against New Zealand, especially in light of the fact that they have all been in good form for their clubs since then," Lancaster said.
"There were some very tight calls, with some experienced players coming back into contention, and I am sure the bench will have a significant impact on the game."
Leicester fly-half Toby Flood, the most experienced player in the 23-man squad with 53 caps, comes onto the bench along with Saracens wing David Strettle.
Manu Tuilagi is expected to be available for England's second Six Nations appointment, against Ireland in Dublin a week on Sunday.
Twelvetrees is not a like-for-like replacement but he has a more rounded game than Tuilagi, offering a kicking game and a presence as a second playmaker outside Farrell.
The 24-year-old is also a powerful ball-carrier and defender, prompting Gloucester's director of rugby Nigel Davies to enthuse that he is the complete package for an inside centre.
England team to play Scotland:
A Goode (Saracens); C Ashton (Saracens), B Barritt (Saracens), B Twelvetrees (Gloucester), M Brown (Harlequins); O Farrell (Saracens), B Youngs (Leicester), J Marler (Harlequins), T Youngs (Leicester), D Cole (Leicester), J Launchbury (Wasps), G Parling (Leicester), T Wood (Northampton), C Robshaw (Harlequins, capt), B Morgan (Gloucester).
Replacements: D Hartley (Northampton), D Wilson (Bath), M Vunipola (Saracens), C Lawes (Northampton), J Haskell (Wasps), D Care (Harlequins), T Flood (Leicester), D Strettle (Saracens).
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