The closure of Imperial Tobacco's Horizon factory in Nottingham was announced two years ago and will lead to over 500 job losses.
Most of the staff will leave next week, with 70 staying on for 18 months as part of the "decommissioning process".
The site's closure has been blamed partly on attitudes to smoking.
Chris Needham, regional organiser for the GMB trade union, said at its height, the firm employed 7,000 staff and made 52 billion cigarettes each year.
Mr Needham said operations would move to Poland and Germany, which will increase profits by Â£320m.
"We're talking about generations that have been manufacturing in Nottingham since 1860," he said.
"The Horizon factory has been part of Imperial Tobacco, worldwide, producing profits in the billions."
Mr Needham said 16 to 17 billion cigarettes - or "sticks" as they are known by staff - were produced last year.
"The issue is about quantities," he said. "And the stigma of smoking has been one of the major factors.
"They [the company] are moving to the Asian markets where the stigma is not as great. Iraq, Syria, Russia, China - these are places I'm sure will be targeted by Imperial Tobacco."
Janet May Dangerfield, who worked at the firm in the 1970s after she left school at the age of 15, expressed her sadness at the firm's demise.
"I'm very shocked and sad because I always thought that would always be there," she said.
"I can remember my first day. I was very nervous but straight away, all the older ones - I think they were called the 'front girls' and 'second front girls' - took me under their wing."
When she moved into the "vast" Horizon factory, Mrs Dangerfield said the size of the site made her and other employees look like "little mice".
Bosses at the factory previously blamed falling sales and an increase in the illegal tobacco trade for their decision to move out of the UK.
History professor John Beckett, from the University of Nottingham, said the business was actually a "major contributor" to the funding required for the city's Queen's Medical Centre.
"It's been in decline ever since the first reports in the 1950s that smoking was bad for your health," he said.
"Gradually, much of the production has been moved abroad, much of it into countries where it's cheaper such as Poland... and the demand here has almost collapsed."
A company spokesman confirmed the plans for closure, but did not offer anyone to comment on the latest developments.

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Matthew Clarke's side-foot finish moved Linfield in front before Coleraine defender David Ogilby was sent-off for two yellows on 67 minutes.
Jamie Mulgrew poked in Linfield's third as they maintained their 100% record.
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His dinked cross picked out the unmarked Burns as the midfielder netted his fifth goal of the campaign while Clarke rifled home from a tight angle at the back post.
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Linfield capitalised with the extra man two minutes later - substitute Mulgrew jinked into the box before prodding the ball beyond keeper Michael Doherty.
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The last pack of English-made cigarettes has rolled off the production line as the country's only tobacco factory prepares to shut.
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