The Owls have lost their last four league matches while the Millers have lost their last five, although they currently sit one place above Wednesday, who now have a new head coach at the helm.
The 46-year-old, who had been in charge of the League One outfit since July 2019, succeeds Tony Pulis, who was sacked in December, with Neil Thompson having been in interim charge for the last two months.
Moore stated that the "opportunity was too much to resist" and he has decided to leave a club challenging for promotion in the third tier for the Owls, who currently sit second bottom of the Championship, six points from safety.
Wednesday will be hoping that Moore will make an immediate impact with the club who have lost their last four matches, including a 3-2 defeat away at Luton Town last weekend, a game which they led at half time 2-0.
The Owls have lacked goals throughout this campaign, having scored just 23 times so far, the joint-fewest along with basement club Wycombe Wanderers.
Moore's task of keeping Wednesday in the Championship will be a challenging one but a victory in midweek would get him and his side off to a good start and could see the Owls move three points behind Birmingham City, who sit just above the drop zone.
Rotherham lost their fourth successive league match by a 1-0 scoreline as they were defeated by promotion hopefuls Reading last weekend.
The Millers went home empty handed for the 18th time this campaign and they remain inside the bottom three, one point above the Owls.
Rotherham can take some confidence into their clash with Sheffield Wednesday, having already beaten them 3-0 in October earlier this campaign.
The Millers are looking to complete a league double over the Owls for the first time and a win could move them two points behind Birmingham.
Sheffield Wednesday Championship form: LWLLLL
Rotherham United Championship form: WLLLLL
Sheffield Wednesday midfielder Liam Shaw is available after serving a two-match suspension for his red card against Birmingham City.
Darren Moore used a 4-2-3-1 formation throughout the campaign with Doncaster and may decide to use the same system in midweek.
Sheffield Wednesday possible starting lineup:
Wildsmith; Palmer, Lees, Borner, Penney; Bannan, Hutchinson; Harris, Brown, Reach; Rhodes
Rotherham United possible starting lineup:
Johansson; Olosunde, Harding, A. MacDonald, Giles; Wing, Barlaser, S. MacDonald; Crooks, Ladapo, Smith
We say: Sheffield Wednesday 2-1 Rotherham United
A turnaround in form is desperately needed for both sides who are at risk of moving further adrift at the bottom if their miserable runs of form continue.
With Darren Moore hoping to put his stamp on his new Sheffield Wednesday squad immediately, we feel a manager bounce could be on the cards, with the hosts to edge out Rotherham at Hillsborough.