The flanker, who had been so impressive in the Dragons pre-season, ruptured knee ligaments during the victory over London Irish on Friday.
His injury leaves Lewis Evans as the only player able to pack down on the openside and the Dragons may be forced to dip into the transfer market.
“Firstly, we are devastated for Darren because he played very well in our warm-up games and was in pole position to start against Zebre,” said director of rugby Rob Beale.
“To have this happen is disastrous for Darren because he is desperate to prove that he is a quality professional player.
“It does leave us with something of a problem because we are running with a 38-man squad and Darren is an important part of that.
“We are sailing close to the wind and if we pick up any more injuries then we will have to go into the market place.
“The first place that we will look is the Premiership and our fixture against the Gwent Select (a 16-10 loss) shows that there is quality there.
“We know what we have got there and have used (Cross Keys captain) Rob Nash in the past and know all about his qualities.
“But we need to get our timing right in terms of recruitment and watching the first few weeks of action will be key to that.”
Waters will be joined on the sidelines by centre Adam Hughes and wing Matthew Pewtner after they suffered hamstring injuries in the Exiles clash.
The Dragons already knew that they would be without wing Tonderai Chavhanga and full-back Jamie Smith but Ashley Smith and Will Harries are back in training.
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