The Auld Brig in Irvine is the only pub to remain open as all other Wetherspoons in Tier 3 areas close from Saturday night.
The Rivergate based premises will stay open because it is still attracting business through the shopping centre.
The company confirmed 46 other pubs will close across the country until restrictions are eased.
Wetherspoon spokesman Eddie Gershon said: “We can confirm that 46 of our 61 pubs in Scotland will close from 6pm Saturday and reopen when restrictions are eased and our pubs can trade more normally.
“The Auld Brigg will remain open as it is part of a shopping centre which is attracting people.
“We look forward to reopening our pubs in due course.”
JD Wetherspoon's boss Tim Martin hit out after Nicola Sturgeon announced Scotland's tier system and criticised more general UK Covid-related restrictions for the pub industry after revealing a sharp fall in sales.
The firm said like-for-like sales for the 15 weeks to November 8 fell by 27.6 per cent.
A statement released by the business earlier this month read: "The Scottish pubs, in particular, are subject to an extremely onerous tier system which, as has been widely reported, is having a serious effect on trade."
Under Tier 3 restrictions, pubs and licensed premises can remain open but must close at 6pm and are banned from serving alcohol.
Around 756 pubs in England, Northern Ireland and the Republic of Ireland have been forced to close for a month due to the second lockdowns - which Wetherspoons said would burn through £14million.
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