Nelson, who suffered 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 Joe Haden, Nelson has been a solid addition this season with 21 tackles.
In addition to Nelson, the Steelers will be without linebacker Mark Barron, another key free-agency acquisition, as he continues to recover from a hamstring injury.