Cueto, who has won 18 senior caps and scored 13 Test tries, missed out on England's opening RBS 6 Nations Championship appointments with Scotland and Italy due to groin and calf muscle problems.
But he sets off on the comeback trail at Ravenhill, hoping to make an immediate statement for the latter section of England's Six Nations campaign.
Cueto replaces Bath wing Nick Abendanon, and Saxons coach Jim Mallinder said: "We know what Mark is capable of, and with him back in the reckoning, this is a good chance for him to regain some match fitness.
"It is tough on Nick Abendanon, who I thought had a great game against Italy A in Exeter last Friday."
Scrum-half Shaun Perry, whose performance for the Saxons in their 34-5 defeat of Italy's second string gained him Six Nations promotion, is replaced by Peter Richards, while former Great Britain rugby league star Chev Walker gains his first international start at union level.
Mallinder added: "This is a good chance for us to have a look at Chev. He did well with the little game time he got last week, and he fully deserves his place."
London Irish centre Mike Catt will captain a Saxons side that also includes a back-row opportunity for Chris Jones, while promising Northampton hooker Dylan Hartley also starts and Newcastle flanker Ben Woods gains a chance on the bench.
"We are lucky to have two quality blindside flankers in Chris Jones and James Haskell," said Mallinder.
"Although James played very well for us last week, we felt that as well as giving us another good lineout option, Chris offers us the experience.
"And we welcome Ben Woods to the squad. He has been playing consistently well for Newcastle, and he will give us back-row cover with Nick Easter now with the senior squad."
England Saxons: M Brown (Harlequins); M Cueto (Sale Sharks), C Walker (Bath), M Catt (London Irish, capt), D Strettle (Harlequins); S Geraghty (London Irish), P Richards (Gloucester); T Payne (Wasps), D Hartley (Northampton), S Turner (Sale Sharks), D Schofield (Sale Sharks), A Brown (Gloucester), C Jones (Sale Sharks), J Scaysbrook (Bath), J Crane (Leicester).
Replacements: A Titterrell (Sale Sharks), N Wood (Gloucester), B Woods (Newcastle), J Haskell (Wasps), R Wigglesworth (Sale Sharks), O Barkley (Bath), N Abendanon (Bath).