North’s club, Northampton Saints, says the winger has a knee injury that requires four weeks of rehabilitation.
That timeframe leaves North unlikely to be involved in Wales’ opening match against Scotland in Cardiff on 3 February.
“George North sustained an injury to his knee during Saints’ defeat to Harlequins on Saturday at Twickenham which will require up to four weeks’ rehabilitation,” Northampton said in a statement.
It is the latest setback for North who missed Wales’ four autumn Tests after suffering a knee injury while on European Champions Cup duty in October.
Wales coach Warren Gatland also has to contend with serious injury problems in the back row ahead of the Six Nations, with Sam Warburton already ruled out of the entire tournament with a knee issue.
Fellow flanker Dan Lydiate could also miss out due to a bicep problem, and No 8 Taulupe Faletau is set to miss the start of the competition, also with a knee injury.
Another No 8, Ross Moriarty, is a concern having missed most of the season with a back injury.