The Glasgow centre is departing early to spend time with his family following the recent arrival of a new baby.
Josh Bayliss, Alex Craig, Will Hurd, Arron Reed, Dylan Richardson and Gus Warr will also miss next Saturday's Test in Montevideo.
All seven players featured in Saturday's 52-11 defeat of Chile.
Ross McCann, Elliot Millar Mills, Smith, Ross Thompson and Glen Young left the tour before the third Test in Santiago.
Lock Ewan Johnson is the only player to play his club rugby outside of Scotland remaining in the squad.
Scotland squad for Uruguay Test
Forwards: Ewan Ashman (Edinburgh), Gregor Brown (Glasgow Warriors), Luke Crosbie (Edinburgh), Scott Cummings (Glasgow Warriors), Rory Darge (Glasgow Warriors), Matt Fagerson (Glasgow Warriors), Patrick Harrison (Edinburgh), Ewan Johnson (Oyonnax), Nathan McBeth (Glasgow Warriors), Javan Sebastian (Edinburgh), Pierre Schoeman (Edinburgh), Rory Sutherland (Oyonnax), Jamie Ritchie (Edinburgh), Murphy Walker (Glasgow Warriors), Max Williamson (Glasgow Warriors).
Backs: Matt Currie (Edinburgh), Jamie Dobie (Glasgow Warriors), Adam Hastings (Gloucester), Ben Healy (Edinburgh), George Horne (Glasgow Warriors), Huw Jones (Glasgow Warriors), Stafford McDowall (Glasgow Warriors), Harry Paterson (Edinburgh), Kyle Rowe (Glasgow Warriors), Kyle Steyn (Glasgow Warriors) Duhan van der Merwe (Edinburgh).