The Cardiff Blues wing picked up the problem in Thursday night's victory over Benetton Treviso.
Halfpenny has been blighted by ankle injuries all season and subsequently missed the entire autumn series and the majority of the RBS 6 Nations due to a similar injury. Now he now looks set for another extended period on the sidelines.
"His ankle is a concern," said Blues head coach Dai Young.
"He has got to see the medics but how serious it is I couldn't tell you.
"He's hobbling about a bit and they've put him on crutches as a precaution.
"I would have thought he is definitely not going to be available for Rodney Parade, even if it's a slight twist it's a week to two weeks.
"So we've got to keep our fingers crossed it's not going to affect him for Wales' warm-up games and so on.
"It's looking very unlikely he'll figure in the two remaining games even if it's a minor injury."
The Blues travel to Rodney Parade to face Newport Gwent Dragons on Friday as the capital city side look to book their place in the Magners League play-offs.