Almost 50 staff are off work because of Covid-19 at the site, the Communication Workers’ Union (CWU) said.
Staff refused to enter the site on Tuesday until a deep clean happened.
Royal Mail confirmed the clean went ahead on Tuesday and caused “minor disruption to service”.
It added that it was “working to resolve any additional concerns with our colleagues and our union”.
The CWU’s Charlie Kelly confirmed that staff will return to the sorting office on Wednesday morning after completion of the deep clean.
The union said 17 staff at the office have tested positive, with 13 of those having been diagnosed since Friday.
Mr Kelly said he now estimates that around 31 staff are currently self-isolating, with around 50 members of staff having been impacted because of the outbreak.
A Royal Mail spokesperson said: “Royal Mail takes the health and safety of its colleagues, its customers and the local communities in which we operate very seriously.
“A number of colleagues have tested positive for coronavirus at the Derry Delivery Office.
“They are now recuperating at home and we wish them a speedy recovery. Some colleagues are also self-isolating.
“We are working to resolve any additional concerns with our colleagues and our union.”
Royal Mail said throughout the coronavirus pandemic it had put in “a range of preventive measures” across their sites to protect customers, staff and the communities in which they operate.
There has been a sharp rise of confirmed cases over recent weeks in the north west region.
There have been 4,292 confirmed cases in the Derry and Strabane council area since March – 1,160 of them were diagnosed in the past seven days.
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