Doran-Jones - a member of the England Elite Player Squad - comes in for Joe Marler (Harlequins) with Alex Corbisiero (London Irish) swapping sides in the front row.
Simpson, another senior EPS player, takes over from Richard Wigglesworth (Saracens) while Abendanon returns in place of Mike Brown (Harlequins).
The Saxons are out to build on their 45-17 win over Italy A at Sixways last weekend when they face the Wolfhounds at Ravenhill.
"We were pleased with the performance given that we went into the game with only three days' preparation but Ireland is a significantly different challenge and there are plenty of areas we need to improve" said Lancaster.
"We're away from home and Ireland will be on the rebound from their defeat against Scotland A as well as looking to avenge their defeat at The Rec against us last year. So it's about stepping up our intensity and focus this week. We'll be going into the game with confidence but also very wary and respectful of what Ireland will bring.
"We've got one or two boys who have come back to us from Portugal where Martin Johnson and the senior coaches were keen to have a look at them. The boys who have come down have all been involved before and know the environment well."
15 Nick Abendanon (Bath Rugby)
14 James Simpson-Daniel (Gloucester Rugby)
13 Manu Tuilagi (Leicester Tigers)
12 Billy Twelvetrees (Leicester Tigers)
11 Ugo Monye (Harlequins)
10 Stephen Myler (Northampton Saints)
9 Joe Simpson (London Wasps)
1 Alex Corbisiero (London Irish)
2 Lee Mears (Bath Rugby)
3 Paul Doran-Jones (Gloucester Rugby)
4 Graham Kitchener (Worcester Warriors)
5 Christian Day (Northampton Saints)
6 James Gaskell (Sale Sharks)
7 Chris Robshaw (Harlequins, captain)
8 Luke Narraway (Gloucester Rugby)
16 James Buckland (London Irish)
17 Joe Marler (Harlequins)
18 George Robson (Harlequins)
19 Andrew Saull (Saracens)
20 Paul Hodgson (London Irish)
21 Brad Barritt (Saracens)
22 Mike Brown (Harlequins)