The Glasgow base, on West George Street, will initially have capacity for 15 people and is in addition to the company's headquarters in Edinburgh.
The technology company said it has a number of employees who make the commute between Scotland's largest city and its capital and the new office will give them the option of working closer to home.
In October the business, headed by chief executive Gareth Williams, moved to a larger Edinburgh site at the Quartermile development in the city and has also increased the size of its Singapore operation this year.
Cathy Wilson, Skyscanner's talent director, said: "The new Glasgow office is a great addition to our bases in Edinburgh, Singapore and Beijing, and allows us to offer even more employment opportunities in Scotland at a time when the country needs it.
"We look forward to attracting some of the finest talent across the central belt to both our Glasgow and Edinburgh office over the coming months."
Skyscanner currently employs 150 people in Scotland plus a further 20 across Singapore and Beijing. It is looking to add 100 people in Scotland during 2013, including web developers, marketing managers and IT service specialists.
Around 30 million people visit the Skyscanner website every day, and the company expects to report £30 million turnover this year.