Staffordshire County Council has given notice that all traffic will be prohibited from using the main Ashbourne Road, between Moorhouse Street and Cromwell Terrace.
Pedestrian access will be maintained and there will be limited access to frontages and businesses.
The move comes at the same time as on going improvement works are taking place in Derby Street.
The notice comes into effect on Monday, May 12, until Sunday, May 25.
The work involves sewer connections to the 60-bedroom Premier Inn hotel and restaurant presently under construction at the end of Ashbourne Road.
A county council spokesman said the work to the Premier Inn hotel would be completed by Severn Trent.
Leek county and district councillor, Charlotte Atkins, said the latest road closure could be another blow for traders following the upheaval the town had suffered from highway work over the last two years.
She said: "We expect more visitors to the town at this time of year.
"This work comes on top of the highway work presently being undertaken by the county council along Derby Street.
"Totally Locally and the Foxlowe are attracting people to the town, but visitors will not return if they can't get through and be able to easily find car parking facilities.
"Two businesses near the centre of town have already closed as traders are going through a hard time. A period of stability is required for the town."
Former town mayor Pam Wood, a resident of Ashbourne Road, said the forthcoming road works would be a test for the town's new road layout.
She said: "It has been noticed during the last few months that traffic has got heavier through the town.
"This closure, which is for something that is out of the ordinary, will test the road network system."
"This latest proposed closure will cause more disruption for the shops in Leek to cope with."
The county council said the preferred alternative route for traffic entering the town from the Ashbourne side would be via Springfield Road, Buxton Road and Ball Haye Street.
Meanwhile construction work is rapidily taking place on the Premier Inn building, which includes a large extension to the rear.
The £4.5 million scheme will create 30 full and part-time jobs when the new premises open.
The company announced in December 2012 that it was to redevelop the Talbot pub site.
Whitbread, the parent company of Premier Inn, told the Post & Times this week that the opening date for the new hotel is currently scheduled for the end of July.
A spokesman for Premier Inn said: "As part of the final works for the Premier Inn, we will be working on its final utility connections.
"For this to take place we have permission to close Ashbourne Road for a brief period.
"The works will be completed as quickly as possible."