Nelson, who sustained a groin injury against the Baltimore Ravens, was a limited participant in practice all week.
He didn’t make the trip to Los Angeles with the team, and former first-round pick Artie Burns will start in his place.
Nelson joined the team in free agency, signing a three-year deal worth up to $25.5 million.
Playing opposite of Joe Haden, Nelson has been a solid addition this season with 21 tackles.
In addition to Nelson, the Steelers will also be without linebacker Mark Barron, another key free agency acquisition, as he continues to recover from a hamstring injury.