Margaret Rice-Jones was chairman at NewBay Software when it was sold to Blackberry and has also held senior positions in Psion, CommProve, Motorola and mobile technology specialist Aircom International.
Ms Rice-Jones is currently chairman at life sciences software firm QUMAS and a non-executive director at telecoms business Openet.
She replaces Irish software entrepreneur Ray Nolan who had been chairman at Skyscanner for three years. Chief operating officer Mark Logan will become a full board member at the Edinburgh company.
The shake up of the board comes two months after Skyscanner took an equity investment from US venture house Sequoia Capital, which has previously backed the likes of Google and Apple, valuing the business at around £500 million.