Souttar, 22, has injured his hip and needs a period of recuperation while Ikpeazu is facing surgery on a foot injury.
The two have been crucial in Hearts' rise to the top of the Scottish league table, two points clear of cross-town rivals Hibs. Indeed, Souttar has started all 14 of their games, leading to his first inclusion in the Scotland scquad during the last international break.
"John will be out for five or six months by the looks of things," manager Craig Levein said. "He landed awkwardly and tore the lining of his hip, which is a blow.
"And while we're on it, Uche will be out for five months as well. This problem we've had with his foot we've managed to finally get to the bottom of. It's a really obscure problem which needs an operation."