Next has announced it will close its store in the Rishworth Centre on September 12 and staff have been offered jobs elsewhere.
The owners of the retail park have planning permission to extend the old Next unit and supermarket chain Aldi is lined up to come in.
Dewsbury lost its WH Smith store in the Princess of Wales precinct in April in the wake of the changing face of retail caused by the pandemic.
Kirklees Council has ambitious plans to transform the town under the £50million Dewsbury Blueprint and Coun Eric Firth, the council’s cabinet member for town centres, said there were more positives than negatives.
“We are all saddened that Next is leaving but I’m sure when Aldi comes in there will be many more jobs for local people.
“Dewsbury has suffered more than most towns due to austerity but I think it will be one of the first towns to bounce back.
“While some of the big brands are disappearing from our high streets, we have lots of independents opening up and that is the future.
“We should be doing all we can to encourage entrepreneurs to start up their own businesses and support them all the way.”
Paul Ellis, president of Dewsbury Chamber of Trade, said while it was never good news to lose major retailers, Aldi had a reputation as a good employer and would bring more jobs.
He added: “Over the last 18 months it has been so difficult for high street traders.
“Next does very well with online shopping and the pandemic sealed its fate in Dewsbury.
“We can’t dwell on the past and life moves forward apace.
“Dewsbury’s regeneration will be driven by independent businesses.”
A spokesman for Next confirmed the closure.
He said: “No move into another unit in Dewsbury is currently planned.”