The Renegades won the bat flip and will bowl first at the SCG in Friday night's game, which Renegades recruit Lyon is skipping to prepare himself for the first Test, starting next week.
Australian white-ball international Adam Zampa, another of the Renegades' recruits, has been confirmed for his first match on home soil since starring in a triumphant World Cup campaign.
The match could be Smith's only appearance for the Sixers, who secured his services again following a blistering cameo last summer.
Smith and former Sixer Lyon will link up with the Australian side for the Perth Test against Pakistan.
Renegades captain Nic Maddinson is making his return from a long-term knee injury suffered playing in the BBL in January.
TEAMS
Sixers: Steve Smith, Josh Philippe (wk), James Vince, Moises Henriques (c), Jordan Silk, Tom Curran, Jack Edwards, Sean Abbott, Ben Dwarshuis, Jackson Bird, Stephen O'Keefe
Renegades: Nic Maddinson (c), Joe Clarke (wk), Jake Fraser-McGurk, Jordan Cox, Aaron Finch, Jono Wells, Will Sutherland, Tom Rogers, Kane Richardson, Adam Zampa, Mujeeb Ur Rahman
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