The holders were held to a 3-3 home draw against their League One opponents, before scoring two extra-time goals in Milton Keynes to keep the defence of their title alive.
On paper, Saturday's visit of Palace, who won 2-0 at West Brom in the last round, should provide an even sterner test.
However, with Tony Pulis' men struggling against relegation in the Premier League, the Welshman may be tempted to make wholesale changes with Hull City set to visit Selhurst Park on Tuesday.
Despite both 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 Hosfield and Nathan Ellington finding the net, while a young Leighton Baines came off the bench.
This will be the first clash between these teams in the FA Cup - a competition Palace have never won and which Wigan triumphed in for the first time last season.
Palace 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, which they subsequently lost.
The men from South London lifted themselves out of the relegation zone with victory over Stoke City last time out in the Premier League, 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.
However, the German could include new loan signings Nicky Maynard and Tyias Browning, who made their debuts for the club last weekend.
Wigan 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, but this weekend's clash is likely to come too soon for the duo.
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