Uwe Rosler's charges will be looking to go as far as they can in this season's competition, especially after Roberto Martinez's tournament-winning heroics last campaign
The holders were held to a 3-3 home draw against MK Dons in the third round, before scoring two extra-time goals in Milton Keynes to keep the defence of their title alive.
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However, Eagles boss Tony Pulis may be tempted to make wholesale changes with Hull City set to visit Selhurst Park on Tuesday.
Surprisingly, despite both sides having played in the top two tiers of English football for the last decade, Wigan and Palace have only met on three previous occasions, garnering one win apiece and a draw.
The only meeting to take place in Wigan ended in a 5-0 victory for the hosts in November 2003, with Andy Liddell, Geoff Horsfield and Nathan Ellington finding the net, while a young Leighton Baines came off the bench.
This will also be the first ever clash between these teams in the FA Cup - a competition Palace have never won, with Wigan winning it for the first time in their history last term.
Palace, moreover, have not featured at this stage of the tournament since the 2009-10 season, when a 2-1 victory at Wolves booked a fifth-round tie with Aston Villa - one they subsequently lost.
The men from South London lifted themselves out of the relegation zone of the Premier League with victory over Stoke City last time out, while Wigan have failed to live up to expectations in the Championship.
However, the Lancashire side's 3-0 defeat to Doncaster Rovers on Saturday was their first loss in seven league matches.
Manager Uwe Rosler will have to make do without Shaun Maloney (hip) and Gary Caldwell (Achilles) for the tie, while Ivan Ramis (groin) is also set to miss out.
The German could, though, include new loan signings Nicky Maynard and Tyias Browning, who made their debuts for the club last weekend.
Wigan also confirmed the acquisition of Chelsea's Josh McEachran on loan on Thursday - and the midfielder could go straight into the squad for the clash as he did not feature in the competition during a spell at Watford earlier in the season.
Jack Hunt and Jerome Thomas are nearing a return for Palace, meanwhile, but this weekend's clash is likely to come too soon for the duo.