The Stockbridge store, set up by TV retail guru Mary Portas and known for its designer bargains, will have a display of shoes donated by the public which will then be sold in the shop.
The appeal is being held to raise money for the charity's Stamp Out Killer Diseases campaign to combat deaths from preventable diseases such as pneumonia, malaria, diarrhoea and measles.
Retail manager Rob McMillan said: "Save the Children want to stop these needless deaths.
"Five pounds is all it takes to save a child's life. With a pair of shoes selling for 50 we will be able to save ten children's lives.
"We want to save hundreds of thousands of lives so please go through your wardrobes and rifle through your shoe racks. Most people own pairs of glitzy shoes that will never to be worn again. Now you can donate them the Save the Children's Appeal and know that they've helped save lives."
The appeal, which runs throughout November and December, is backed by an online auction of shoes donated by celebrities including Samantha Cameron, Jonathan Ross, and Sadie Frost. See www.savethechildren.org.uk/killerheels for details.
Designer shoes have also been donated by fashion houses and stores including Nicole Farhi, Betty Jackson and ASOS.