The Terriers have promotion hopes and are currently fifth in the second tier, while the Tykes are rock bottom and in severe relegation danger.
Both of these clubs are previous winners of the FA Cup, with Barnsley lifting the trophy in 1912 and Huddersfield doing so 10 years later.
This is the Terriers' first appearance in the fourth round since 2018 after they knocked out Premier League strugglers Burnley in round three.
Huddersfield were in action in midweek as they beat Derby County 2-0 on Wednesday night to move back into the Championship playoffs.
It is now 11 matches without defeat in all competitions for the Terriers and they are on their longest unbeaten run in the second tier of English football since 1965.
In contrast, Barnsley have lost four successive matches – most recently against Cardiff on Wednesday night – and are eight points adrift of safety in the Championship.
Poya Asbaghi's only win in his 11 games in charge so far came in the previous round of this competition, when the Tykes squeezed past League Two side Barrow with a thrilling 5-4 victory after extra time.
The South Yorkshire outfit are yet to win away from home this season and have lost nine of their last 10 matches on the road.
This is the club's third successive season in the FA Cup fourth round after going six years without getting past round three; last season, they reached the fifth round before losing to Chelsea.
For any fans looking for a glimmer of hope, Barnsley are unbeaten in their last four matches against Huddersfield; the two sides played out a 1-1 draw at Oakwell in their league meeting earlier this season.
Jordan Rhodes is also likely to get the nod upfront after coming off the bench to score his first goal of the season against Derby in midweek.
January signing Jamal Blackman could be handed a debut between the sticks, while fellow new arrival Carel Eiting may start for the first time.
Barnsley's deadline day signings Amine Bassi and Domingos Quina both made their debuts in midweek against Cardiff and should feature again here.
Carlton Morris, who scored twice as a substitute against Barrow in round three, is in contention to start after returning from a period of self-isolation.
Huddersfield Town possible starting lineup:
Blackman; Pipa, Pearson, Sarr, Ruffels; Holmes, Eiting, High, Koroma; Rhodes, Campbell
Barnsley possible starting lineup:
Walton; Andersen, Moon, Helik; J. Williams, Quina, Gomes, Bassi, Vita; Morris, Leya Iseka
We say: Huddersfield Town 2-0 Barnsley
The FA Cup third round provided Barnsley with some respite from their league struggles, but they only just edged past a side two divisions below them. With a run of defeats following in the Championship, we expect them to lose again here and Huddersfield to continue their impressive unbeaten run.
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