England international Simpson-Daniel, who has not played Test rugby since last season's RBS 6 Nations Championship, moves from wing to centre for the Tigers' Kingsholm visit.
And given his prodigious footballing ability, it could prove a shrewd move by Gloucester head coach Dean Ryan.
Simpson-Daniel will partner England centre Anthony Allen in midfield, and with Ryan Lamb at fly-half and Iain Balshaw on the wing, Gloucester's back division has quality written all over it.
Ryan said: "The team is greatly changed from the one that beat Northampton last Saturday, but it is still very exciting.
"And to have the option of shifting a creative player of James Simpson-Daniel's quality into the centre is an added bonus.
"We would like to get his hands on the ball a bit more, and this positional switch will hopefully allow us to do that."
Ryan's main concern has revolved around the front-row, where Italian forward Carlos Nieto is absent due to RBS 6 Nations commitments and fellow prop Christian Califano misses out due to a broken thumb.
Jack Forster moves into the side at tighthead, partnering front-row colleagues Nick Wood and Olivier Azam, while lock Will James takes over from Italy Test skipper Marco Bortolami.
Ryan added: "We have been disrupted this week with a number of issues regarding our prop situation, but we have enough quality in this area of our squad to cope.
"This is a game we are thoroughly looking forward to. Leicester are an outstanding team, they are leaders of the Premiership and are a tremendously resourceful side that we respect fully."
Tigers, two places and six points above Gloucester, are strongly affected by international call-ups, but Irish lock Leo Cullen returns as skipper, and there are also call-ups for backs Sam Vesty, Tom Varndell and Ian Humphreys.
Apart from Leicester's sizeable England contingent being absent, fly-half Andy Goode rests a groin injury and wing Seru Rabeni misses out due to a calf muscle problem.
Leicester head coach Pat Howard said: "We have obviously had to make changes, and Gloucester are missing a couple of players for the international games, including Marco Bortolami, who has been a fantastic signing for them in terms of leadership.
"They have got some sharp backs with genuine pace and a nice, physical pack. We are looking forward to it.
"There is plenty of incentive for Gloucester, but we want to raise our game too, because they are just behind us and we know they are going to be right up there."