Gayle has not featured on the international stage since September and has struggled with a back injury although he recently played in South Africa's 'Ram Slam T20' tournament.
West Indies said in a statement that he had "been replaced due to injury" without offering any further details.
Winward Islands opener Smith has been in excellent form in regional competition with two half-centuries and a ton in his last three games but he has not played a test for West Indies since 2011.
The Caribbean side will play three tests in South Africa starting on Dec. 10 in Centurion.
(Reporting by Simon Evans, editing by Tony Jimenez)
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