Betts, the most experienced second-row forward in the country, injured his knee in August, just as he was running into his best form after missing the start of the season following a major shoulder operation, and his attempts at a comeback have brought on a recurrence.
He has damage to his anterior cruciate ligament and will need surgery that could even see him missing the start of next season.
"It's a bitter blow," said the Wigan coach, John Monie, who had hoped to have Betts available for this month's play-off series. "But, knowing Denis, he will be back as soon as possible."
That return will not, however, be in time for Great Britain's three Tests against New Zealand this autumn. Betts, who has also recently suffered the personal tragedy of the death of his mother, would have been an automatic selection in the squad, but now Andy Goodway is likely to look to the youthful pairing of Adrian Morley and Paul Sculthorpe.
With another second-row man, Mick Cassidy, sidelined for one more match through suspension, Wigan will rely on their young forwards, Simon Haughton and Lee Gilmour, in the early stages of the play-offs.
Wigan are set to step up their bid to sign Featherstone's Karl Pratt and are also interested in his team-mate, the 18-year-old prop forward Stuart Dickens.
Gateshead have signed their 15th Australian as they prepare for their first season in Super League: the Parramatta winger, Ian Herron. He is regarded as one of the best goalkickers in Australia and the new franchise's coach, Shaun McRae, said that landing their goals would be an essential element for the club next season.
Herron, formerly with McRae's old club, St George, does not count on the overseas quota because he has Irish parents - and apparently has ambitions to gain international representative honours with Ireland.
Gateshead are anxiously awaiting news of another of their recruits: the Canterbury forward Tony Grimaldi, who injured a shoulder scoring a try in Sunday's Grand Final defeat by Brisbane.
Grimaldi, who is due to arrive with the rest of the Australian contingent after Christmas, is visiting a specialist in Sydney to determine the extent of the injury.
Halifax's Australian forward, Des Clark, will be fit to face Leeds in the play-off match at Headingley on Sunday, despite being carried off in last weekend's fixture between the two clubs after taking a knee to the head.
Clark has joined his fellow-countryman, David Bouveng, in agreeing a new, two-year contract at Halifax.Reuse content