Asymmetric total synthesis of (−)-sila-mesembranol, the silicon analog of the natural alkaloid (−)-mesembranol has been achieved in 3.3% yield over 11 steps. The chiral silicon center was enantioselectively constructed via the asymmetric expansion of a silacyclobutane ring. The synthetic (−)-sila-mesembranol in mice exhibits better antidepressant effects than its carbon counterpart.