Mathieu picked up the injury during the third quarter of the Cardinals' 30-10 victory over the St Louis Rams yesterday, collapsing when jogging off the field after a big hit by Rams running back Isaiah Pead.
The rookie will undergo an MRI scan later today, but Arians is fearing the worst at this early stage.
"[It] appears to be an ACL. We don't know for sure. We'll wait and see. That's just an early prognosis of the exam that we have right now. He'll go through the MRI and all the rest of the tests, and just keep our fingers crossed," Arians told reporters.
The Cardinals coach admitted that the injury would be a big blow to his side as he believes that Mathieu was on course to be named the defensive rookie of the year.
"To me, he's a lock. I don't know if anybody else has played as much as he's played and all the positions he's played. I just wish that [Rams punter Johnny Hekker] kicked that damn ball to Patrick [Peterson]," Arians added.
Mathieu had made 63 tackles since coming into the team, the second best tally on the Cardinals roster.