Ireland pair Stuart McCloskey and Josh van der Flier will make their international debuts in Saturday's Six Nations encounter with England at Twickenham.
Jared Payne failed to recover in time from a hamstring injury, so Ulster team-mate McCloskey will play at inside centre with Robbie Henshaw switching to 13.
Like McCloskey, Van der Flier has impressed domestically this season and the Leinster flanker comes in for Sean O'Brien - who is ruled out for the rest of the tournament with a hamstring injury sustained in the 10-9 defeat to France in round two.
A shoulder injury has also curtailed Dave Kearney's Six Nations, so Keith Earls takes his place on the wing, while Mike Ross returns in the front row.
Ireland's hopes of defending the Six Nations are increasingly slim after they started with a 16-16 draw against Wales before the loss in France.
New Zealander Schmidt also includes an uncapped face on the bench in the shape of lock Ultan Dillane, while Simon Zebo and Cian Healy return among the replacements.
Ireland team to face England: Rob Kearney, Andrew Trimble, Robbie Henshaw, Stuart McCloskey, Keith Earls, Jonathan Sexton, Conor Murray; Jack McGrath, Rory Best, Mike Ross, Donnacha Ryan, Devin Toner, CJ Stander, Josh van der Flier, Jamie Heaslip.
Replacements: Richard Strauss, Cian Healy, Nathan White, Ultan Dillane, Rhys Ruddock, Eoin Reddan, Ian Madigan, Simon Zebo