He replaces Kees Koolen who moves to become chairman of Booking.com after serving as CEO since September 2008.
Huston has spent eight years with Microsoft, most recently being responsible for its consumer and advertising businesses in 40 countries.
From 2005 to 2008 he was president and CEO of Microsoft Japan.
A former McKinsey consultant and advisor to the Canadian government, before joining Microsoft, Huston was senior vice president of Starbucks Corporation where he was in charge acquisitions and product development.
Huston joins the Priceline-owned Booking.com at a critical time for the company as it looks to continue its rapid growth of recent years, establishing a portfolio of 165,000 hotel properties in 43 countries, and run from 50 offices around the world.