The Yorkshire outfit have overcome Conference side Macclesfield Town and League Two's Rochdale to reach round five.
Next up for the three-time winners is a visit from Chris Powell's Championship strugglers, with the sides having drawn 1-1 at The Valley in December.
Wednesday are searching for a last-eight appearance for the first time since they were defeated 2-0 by Wimbledon in March 1997.
Their recent record in the competition leaves much to be desired, with this just the club's fourth fifth-round appearance since then.
A win on Saturday would leave Stuart Gray's men just 90 minutes away from a first Wembley appearance since four visits in 1993.
Then managed by Trevor Francis, Wednesday suffered heartbreak against Arsenal in the League Cup final, before defeating near-rivals Sheffield United in the semi-final of the FA Cup.
However, Wednesday would go on to suffer an agonising defeat in a replay in the final, with Arsenal once again inflicting the misery through Andy Linighan's 120th-minute winner in extra time.
Wednesday head into the fixture on the back of a 3-0 loss to Wigan Athletic, but the side will take confidence from an 11-match unbeaten run in all competitions that preceded that defeat.
Midfielder Jose Semedo will miss out against his former club after fracturing his fibula against Wigan, and his absence means Gary Gardner could make his debut after joining on a loan deal from Aston Villa, though Giles Coke is another option following the completion of a three-match ban.
Charlton - whose solitary victory in the competition came in 1947 - are seeking some welcome relief from a six-match winless league run that has seen them slip into the Championship relegation zone.
Powell has witnessed his side suffer four straight defeats in the league, including a disappointing 2-0 setback to Birmingham City at the Valley on Saturday.
Victory would see Charlton's first foray into the quarter-finals since 2006, where the club were defeated 4-2 in a replay by Middlesbrough.
Charlton have thus far seen off challenges from Oxford United and Huddersfield Town, and have no fresh injury worries ahead of the visit to Hillsborough.
