"It is obviously disappointing for Jonny to receive an injury just when he was back playing fantastic rugby, but he has enormous strength of character and I am sure he will come back stronger despite this blow," said Newcastle's rugby director Steve Bates.
Wilkinson had only just returned to the Newcastle side after a six-month absence following shoulder surgery.
Since guiding England to World Cup glory in 2003, Wilkinson has suffered injuries to his arm, kidney, shoulder, knee, ankle, groin and abductor muscle, as well as undergoing an operation to remove his appendix.
The latest setback could well see him miss all four of England's autumn internationals next month.
"The England coaching and medical teams are in close contact with Newcastle Falcons regarding Jonny Wilkinson" said an RFU statement.
"A further comment will be made after they receive the results of the specialist's review of his injured left knee."