Whitson, 57, is making her eighth career spacewalk, surpassing the record of seven previously held by American Suni Williams.
The spacewalk formally began at 7:29 am (local time) when Whitson and Shane Kimbrough switched their spacesuits to battery power before venturing outside the airlock and into the vacuum of space.
"Be safe and enjoy your time out," said French astronaut Thomas Pesquet as the hatch opened.
"I will be waiting for you."
The goal of the spacewalk is to continue upgrading the International Space Station for the arrival of commercial spaceships in the years to come.
SpaceX and Boeing are currently designing crew vehicles that will begin flying people to the ISS as early as next year.