Burrell forms an exciting centre partnership with Bath’s Jonathan Joseph in a backline that is largely unchanged from the previous outing, against Australia in November.
Hartley gets the nod at hooker ahead of Leicester Tigers man Tom Youngs, who is on the bench.
Saints trio Calum Clark, Christian Day and Alex Corbisiero were released ahead of the game, while Stephen Myler suffered a calf strain that ruled him out. Tom Wood, Courtney Lawes and Ben Foden are also injured.
The inclusion of Hartley and Burrell means there will be three Northampton players involved at the Millennium Stadium, with George North lining up for the home side.
Tighthead prop Kieran Brookes, who will join Saints from Newcastle this summer, is on the England bench.
“We’ve had to make some tight calls but we are excited about the side selected for what will be a big challenge,” said England head coach Stuart Lancaster.
“JJ (Joseph) has been one of the form centres in the country. He and Luther have trained well together and this is a big opportunity for both of them.”
Wales: Halfpenny; Cuthbert, Davies, Roberts, North; Biggar, Webb; Jenkins, Hibbard, Lee; Ball, Wyn-Jones; Lydiate, Warburton, Faletau.
Replacements: Baldwin, James, Jarvis, Charteris, Tipuric, Phillips, Priestland, Williams.
England: Brown; Watson, Joseph, Burrell, May; Ford, B Youngs; Marler, Hartley, Cole; Attwood, Kruis; Haskell, Robshaw, B Vunipola.
Replacements: T Youngs, M Vunipola, Brookes, Croft, Easter, Wigglesworth, Cipriani, Twelvetrees.