Uwe Rosler's Latics have already beaten top-flight opposition in Crystal Palace and travel to Wales with an unlikely defense of their FA Cup crown still possible.
The Latics are on a 10-match unbeaten run in the world's oldest football competition, including a famous 1-0 triumph over Manchester City in last season's final when Roberto Martinez was at the helm.
Wigan has since dropped out of the Premier League, meaning that Uwe Rosler's men would be the first team in 34 years to win the competition from outside the top flight if they can repeat their success, with West Ham the last team to achieve the feat in 1980.
Cardiff has failed to register a victory over the Lancashire side since a 1-0 win March 1997, a run that stretches back for 10 matches, though Saturday's encounter will mark the first meeting between the two teams since April 2005.
Wigan has already beaten Premier League opposition to get this far, as goals from Ben Watson and James McClean ensured a 2-1 victory over Crystal Palace in round four.
Both Rosler and Cardiff boss Ole Gunnar Solskjaer joined their respective clubs this season. The former has fared slightly better in his new role, with eight wins from 15 matches, while the latter has emerged victorious from three of eight.
The pair has a history as cross-town rivals for two years from their playing days at Manchester United and City and their pasts are further intertwined, with the Norwegian having replaced Rosler as Molde boss in November 2010, despite the German staving off the threat of relegation that season by going unbeaten in the last eight games.
Solskjaer will be wary of a potential banana skin, with his side having recorded just two wins from its last seven matches in all competitions, while the last two fixtures have seen the club fail to score.
The Bluebirds manager - a two-time winner of the competition as a player in 1999 and 2004 - will hope that striker Fraizer Campbell can continue his form in the cup, with the one-time England international netting in the wins over Newcastle and Bolton in previous rounds.
Juan Cala could make his Cardiff debut at center back after signing on a free from Sevilla but club captain Mark Hudson remains a doubt with a hamstring injury.