O'Brien's latest onslaught came on Friday at the Global Economic Forum in Dublin.
It followed a recent flurry of criticism by the shareholder, who has long been calling for the group to close The Independent. O'Brien is also at odds with IN&M chief executive Gavin O'Reilly and the board over the repayment of its €200m debt.
O'Brien said: "There's no point in us as a company subsidising a newspaper that really nobody wants to read in the United Kingdom. It's not a relevant newspaper any more and this newspaper's going to be closed at Christmas."
A spokesman for IN&M said: "Denis O'Brien has made clear his hostility. But this is his most outspoken criticism yet and it does nothing to motivate the staff who work at the newspaper."