Smith-Schuster, who didn't practice all week, entered the concussion protocol after taking a hit in last week's game against the Jacksonville Jaguars.
Smith-Schuster is the Chiefs' second-leading receiver with 46 catches for 615 yards. He also has two touchdowns.
The Chiefs will also play against the Chargers without another one of their top wide receivers, Mecole Hardman. He was placed on the injured reserve list this week with an abdominal issue.
Marquez Valdes-Scantling, the Chiefs' third-leading receiver with 26 catches, will be available to play against the Chargers. He missed some practice time this week with an illness. The Chiefs' other wide receivers on the active roster are Kadarius Toney, Justin Watson and rookie Skyy Moore.
Toney, recently acquired in a trade with the New York Giants, scored his first NFL touchdown and led the team's wide receivers in catches with four last week. Watson and Moore have combined for 14 receptions and two touchdowns.